Integrin receptor antagonists

ABSTRACT

The present invention relates to compounds and derivatives thereof, their synthesis, and their use as vitronectin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the vitronectin receptors ανβ3 and/or ανβ5 and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, viral disease, and tumor growth.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention is related to U.S. provisional applications Ser.No. 60/069,910, filed Dec. 17, 1997; 60/083,251, filed Apr. 27, 1998;and 60/092,588, filed Jul. 13, 1998; the contents of each of which arehereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to compounds and derivatives thereof,their synthesis, and their use as integrin receptor antagonists. Moreparticularly, the compounds of the present invention are antagonists ofthe integrin receptors ανβ3, ανβ5, and/or ανβ6 and are useful forinhibiting bone resorption, treating and preventing osteoporosis, andinhibiting vascular restenosis, diabetic retinopathy, maculardegeneration, angiogenesis, atherosclerosis, inflammation, woundhealing, viral disease, tumor growth, and metastasis.

BACKGROUND OF THE INVENTION

It is believed that a wide variety of disease states and conditions canbe mediated by acting on integrin receptors and that integrin receptorantagonists represent a useful class of drugs. Integrin receptors areheterodimeric transmembrane receptors through which cells attach andcommunicate with extracellular matrices and other cells (See S. B. Rodanand G. A. Rodan, "Integrin Function In Osteoclasts", Journal ofEndocrinology, Vol. 154, S47-S56 (1997), which is incorporated byreference herein in its entirety).

In one aspect of the present invention, the compounds herein are usefulfor inhibiting bone resorption. Bone resorption is mediated by theaction of cells known as osteoclasts. Osteoclasts are largemultinucleated cells of up to about 400 mm in diameter that resorbmineralized tissue, chiefly calcium carbonate and calcium phosphate, invertebrates. Osteoclasts are actively motile cells that migrate alongthe surface of bone, and can bind to bone, secrete necessary acids andproteases, thereby causing the actual resorption of mineralized tissuefrom the bone. More specifically, osteoclasts are believed to exist inat least two physiological states, namely, the secretory state and themigratory or motile state. In the secretory state, osteoclasts are flat,attach to the bone matrix via a tight attachment zone (sealing zone),become highly polarized, form a ruffled border, and secrete lysosomalenzymes and protons to resorb bone. The adhesion of osteoclasts to bonesurfaces is an important initial step in bone resorption. In themigratory or motile state, the osteoclasts migrate across bone matrixand do not take part in resorption until they again attach to bone.

Integrins are involved in osteoclast attachment, activation andmigration. The most abundant integrin in osteoclasts, e.g., in rat,chicken, mouse and human osteoclasts, is an integrin receptor known asανβ3, which is thought to interact in bone with matrix proteins thatcontain the RGD sequence. Antibodies to ανβ3 block bone resorption invitro indicating that this integrin plays a key role in the resorptiveprocess. There is increasing evidence to suggest that ανβ3 ligands canbe used effectively to inhibit osteoclast mediated bone resorption invivo in mammals.

The current major bone diseases of public concern are osteoporosis,hypercalcemia of malignancy, osteopenia due to bone metastases,periodontal disease, hyperparathyroidism, periarticular erosions inrheumatoid arthritis, Paget's disease, immobilization-inducedosteopenia, and glucocorticoid-induced osteoporosis. All of theseconditions are characterized by bone loss, resulting from an imbalancebetween bone resorption, i.e. breakdown, and bone formation, whichcontinues throughout life at the rate of about 14% per year on theaverage. However, the rate of bone turnover differs from site to site;for example, it is higher in the trabecular bone of the vertebrae andthe alveolar bone in the jaws than in the cortices of the long bones.The potential for bone loss is directly related to turnover and canamount to over 5% per year in vertebrae immediately following menopause,a condition which leads to increased fracture risk.

In the United States, there are currently about 20 million people withdetectable fractures of the vertebrae due to osteoporosis. In addition,there are about 250,000 hip fractures per year attributed toosteoporosis. This clinical situation is associated with a 12% mortalityrate within the first two years, while 30% of the patients requirenursing home care after the fracture.

Individuals suffering from all the conditions listed above would benefitfrom treatment with agents which inhibit bone resorption.

Additionally, ανβ3 ligands have been found to be useful in treatingand/or inhibiting restenosis, i.e. recurrence of stenosis aftercorrective surgery on the heart valve, atherosclerosis, diabeticretinopathy, macular degeneration, and angiogenesis, i.e. formation ofnew blood vessels. Moreover, it has been postulated that the growth oftumors depends on an adequate blood supply, which in turn is dependenton the growth of new vessels into the tumor; thus, inhibition ofangiogenesis can cause tumor regression in animal models (See Harrison'sPrinciples of Internal Medicine 12th ed., 1991, which is incorporated byreference herein in its entirety). Therefore, ανβ3 antagonists whichinhibit angiogenesis can be useful in the treatment of cancer byinhibiting tumor growth (See e.g., Brooks et al., Cell, 79:1157-1164(1994), which is incorporated by reference herein in its entirety).

Moreover, compounds of this invention can also inhibitneovascularization by acting as antagonists of the integrin receptor,ανβ5. A monoclonal antibody for ανβ5 has been shown to inhibitVEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoicmembrane model (See M. C. Friedlander, et al., Science 270, 1500-1502,(1995), which is incorporated by reference herein in its entirety).Thus, compounds that antagonize ανβ5 are useful for treating andpreventing macular degeneration, diabetic retinopathy, tumor growth, andmetastasis.

Additionally, compounds of the instant invention can inhibitangiogenesis and inflammation by acting as antagonists of the integrinreceptor, ανβ6, which is expressed during the later stages of woundhealing and remains expressed until the wound is closed (SeeChristofidou-Solomidou, et al., "Expression and Function of EndothelialCell αν Integrin Receptors in Wound-Induced Human Angiogenesis in HumanSkin/SCID Mice Chimeras," American Journal of Pathology, Vol. 151, No.4, pp. 975-983 (October 1997), which is incorporated by reference hereinin its entirety). It is postulated that ανβ6 plays a role in theremodeling of the vasculature during the later stages of angiogenesis.Also, ανβ6 participates in the modulation of epithelial inflammation andis induced in response to local injury or inflammation (See Xiao-ZhuHuang, et al., "Inactivation of the Integrin β6 Subunit Gene Reveals aRole of Epithelial Integrins in Regulating Inflammation in the Lungs andSkin," Journal of Cell Biology, Vol. 133, No. 4, pp. 921-928 (May 1996),which is incorporated by reference herein in its entirety). Accordingly,compounds that antagonize ανβ6 are useful in treating or preventingcancer by inhibiting tumor growth and metastasis.

In addition, certain compounds of this invention antagonize both theανβ3 and ανβ5 receptors. These compounds, referred to as "dual ανβ3/ανβ5antagonists," are useful for inhibiting bone resorption, treating andpreventing osteoporosis, and inhibiting vascular restenosis, diabeticretinopathy, macular degeneration, angiogenesis, atherosclerosis,inflammation, tumor growth, and metastasis.

In addition, certain compounds of this invention are useful as mixedανβ3, ανβ5, and ανβ6 receptor antagonists.

It is therefore an object of the present invention to provide compoundswhich are useful as integrin receptor antagonists.

It is another object of the present invention to provide compounds whichare useful as ανβ3 receptor antagonists.

It is another object of the present invention to provide compounds whichare useful as ανβ5 receptor antagonists.

It is another object of the present invention to provide compounds whichare useful as ανβ6 receptor antagonists.

It is another object of the present invention to provide compounds whichare useful as dual ανβ3/ανβ5 receptor antagonists.

It is another object of the present invention to provide compounds whichare useful as mixed ανβ3, ανβ5, and ανβ6 receptor antagonists.

It is another object of the present invention to provide pharmaceuticalcompositions comprising integrin receptor antagonists.

It is another object of the present invention to provide methods formaking the pharmaceutical compositions of the present invention.

It is another object of the present invention to provide methods foreliciting an integrin receptor antagonizing effect in a mammal in needthereof by administering the compounds and pharmaceutical compositionsof the present invention.

It is another object of the present invention to provide compounds andpharmaceutical compositions useful for inhibiting bone resorption,restenosis, atherosclerosis, inflammation, viral disease, diabeticretinopathy, macular degeneration, angiogenesis, tumor growth, andmetastasis.

It is another object of the present invention to provide compounds andpharmaceutical compositions useful for treating osteoporosis.

It is another object of the present invention to provide methods forinhibiting bone resorption, restenosis, atherosclerosis, inflammation,viral disease, diabetic retinopathy, macular degeneration, angiogenesis,tumor growth, and metastasis.

It is another object of the present invention to provide methods fortreating osteoporosis.

These and other objects will become readily apparent from the detaileddescription which follows.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR1##wherein W is selected from the group consisting of ##STR2## a 5- or6-membered monocyclic aromatic or nonaromatic ring system having 0, 1,2, 3 or 4 heteroatoms selected from the group consisting of N, O, and Swherein the ring nitrogen atoms are unsubstituted or substituted withone R¹ substituent and the ring carbon atoms are unsubstituted orsubstituted with one or two R¹ substituents, and

a 9- to 14-membered polycyclic ring system, wherein one or more of therings is aromatic, and wherein the polycyclic ring system has 0, 1, 2, 3or 4 heteroatoms selected from the group consisting of N, O, and S, andwherein the ring nitrogen atoms are unsubstituted or substituted withone R¹ substituent and the ring carbon atoms are unsubstituted orsubstituted with one or two R¹ substituents;

X is selected from the group consisting of

--(CH₂)_(v) --, wherein any methylene (CH₂) carbon atom is eitherunsubstituted or substituted with one or two R¹ substitutents; and a 5-or 6-membered monocyclic aromatic or nonaromatic ring system having 0,1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, andS wherein the ring nitrogen atoms are unsubstituted or substituted withone R¹ substituent and the ring carbon atoms are unsubstituted orsubstituted with one or two R¹ substituents;

Y is selected from the group consisting of

--(CH₂)_(m) --,

--(CH₂)_(m) --O--(CH₂)_(n) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --,

--(CH₂)_(m) --S--(CH₂)_(n) --,

--(CH₂)_(m) --SO--(CH₂)_(n) --,

--(CH₂)_(m) --SO₂ --(CH₂)_(n) --,

--(CH₂)_(m) --O--(CH₂)_(n) --O--(CH₂)_(p) --,

--(CH₂)_(m) --O--(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,

--(CH₂)_(m) --O--(CH₂)_(n) --S--(CH₂)_(p) --,

--(CH₂)_(m) --S--(CH₂)_(n) --S--(CH₂)_(p) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --S--(CH₂)_(p) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --O--(CH₂)_(p) --,

--(CH₂)_(m) --S--(CH₂)_(n) --O--(CH₂)_(p) --, and

--(CH₂)_(m) --S--(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,

wherein any methylene (CH₂) carbon atom in Y, other than in R⁴, can besubstituted by one or two R³ substituents;

Z is a 5 membered aromatic or nonaromatic mono- or bicyclic ring systemhaving 0 to 3 heteroatoms selected from the group consisting of N, O,and S, and wherein the ring system is either unsubstituted orsubstituted with 0, 1, 2, or 3 oxo or thio substituents, and eitherunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of R¹⁰, R¹¹, and R¹² ;

wherein R¹ and R² are each independently selected from the groupconsisting of

hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl,C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆ alkyl, aryl, arylC₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈alkyl, (C₁₋₆ alkyl)_(p) amino, (C₁₋₆ alkyl)_(p) amino C₁₋₈ alkyl, C₁₋₄alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl,hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, C₁₋₆alkyloxy-C₁₋₆ alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,trifluoroethoxy, C₁₋₈ alkyl-S(O)_(p), (C₁₋₈ alkyl)_(p) aminocarbonyl,C₁₋₈ alkyloxycarbonylamino, (C₁₋₈ alkyl)_(p) aminocarbonyloxy, (arylC₁₋₈ alkyl)_(p) amino, (aryl)_(p) amino, aryl C₁₋₈ -alkylsulfonylamino,and C₁₋₈ alkylsulfonylamino; or two R¹ substituents, when on the samecarbon atom, are taken together with the carbon atom to which they areattached to form a carbonyl group;

each R³ is independently selected from the group consisting of

hydrogen,

aryl,

C₁₋₁₀ alkyl,

aryl--(CH₂)_(r) --O--(CH₂)_(s) --,

aryl--(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,

halogen,

hydroxyl,

oxo,

trifluoromethyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

(C₁₋₆ alkyl)pamino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

or two R³ substituents, when on the same carbon atom are taken togetherwith the carbon atom to which they are attached to form a carbonyl groupor a cyclopropyl group,

wherein any of the alkyl groups of R³ are either unsubstituted orsubstituted with one to three R¹ substituents, and provided that each R³is selected such that in the resultant compound the carbon atom or atomsto which R³ is attached is itself attached to no more than oneheteroatom;

each R⁴ is independently selected from the group consisting of

hydrogen,

aryl,

aminocarbonyl,

C₃₋₈ cycloalkyl,

amino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl,

(aryl C₁₋₅ alkyl)_(p) aminocarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

aminosulfonyl,

C₁₋₈ alkylaminosulfonyl,

(aryl)_(p) aminosulfonyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonyl,

arylsulfonyl,

arylC₁₋₆ alkylsulfonyl,

C₁₋₆ alkylthiocarbonyl,

arylthiocarbonyl, and

aryl C₁₋₆ alkylthiocarbonyl,

wherein any of the alkyl groups of R⁴ are either unsubstituted orsubstituted with one to three R¹ substituents;

R⁵ and R⁶ are each independently selected from the group consisting of

hydrogen;

C₁₋₁₀ alkyl,

aryl,

aryl--(CH₂)_(r) --O--(CH₂)_(s) --,

aryl--(CH₂)_(r) --(O)_(p) --(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --)

aryl--(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C1-5 alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

(C₁₋₆ alkyl)_(p) amino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₋₆ alkyl,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylanmino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl;

or R⁵ and R⁶ are taken together with the carbon atom to which they areattached to form a carbonyl group,

wherein any of the alkyl groups of R⁵ or R⁶ are either unsubstituted orsubstituted with one to three R¹ substituents, and provided that each R⁵and R⁶ are selected such that in the resultant compound the carbon atomto which R⁵ and R⁶ are attached is itself attached to no more than oneheteroatom;

R⁷ and R⁸ are each independently selected from the group consisting of

hydrogen,

C₁₋₁₀ alkyl,

aryl,

aryl--(CH₂)_(r) --O--(CH₂)_(s) --,

aryl--(CH₂)_(r) --S(O)_(p) --(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl--(CH₂)_(r) N(R⁴)--C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) N(R⁴)--(CH₂)_(s) --,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

(C₁₋₆ alkyl)_(p) amino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylcarbonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

arylaminocarbonylamino,

(aryl C₁₋₈ alky)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylanmino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl, and

C₇₋₂₀ polycyclyl C₀₋₈ alkylsulfonylamino;

wherein any of the alkyl groups of R⁷ and R⁸ are either unsubstituted orsubstituted with one to three R¹ substituents, and provided that each R⁷and R⁸ are selected such that in the resultant compound the carbon atomto which R⁷ and R⁸ are attached is itself attached to no more than oneheteroatom;

R⁹ is selected from the group consisting of

hydrogen,

C₁₋₈ alkyl,

aryl,

aryl C₁₋₈ alkyl,

C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

C₁₋₈ alkylaminocarbonylmethylene, and

C₁₋₈ dialkylaminocarbonylmethylene;

R¹⁰ , R¹¹, and R¹² are each independently selected from the groupconsisting of

hydrogen,

C₁₋₈ alkyl,

aryl,

halogen,

hydroxyl,

oxo,

aminocarbonyl,

C₃₋₈ cycloalkyl,

amino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl,

hydroxycarbonyl,

(aryl C₁₋₅ alkyl)_(p) aminocarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

aminosulfonyl,

C₁₋₈ alkylaminosulfonyl,

(aryl)_(p) aminosulfonyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonyl,

C₁₋₆ alkylsulfonyl,

arylsulfonyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylthiocarbonyl,

arylthiocarbonyl,

aryl C₁₋₆ alkylthiocarbonyl,

aryl--(CH₂)_(r) --O--(CH₂)_(s) --,

aryl--(CH₂)_(r) --S(O)p--(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) amino,

aminocarbonyl C₁₋₆ alkyl,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkylpaminocarbonyl amino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylanmino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

wherein any of the alkyl groups of R¹⁰, R¹¹, and R¹² are eitherunsubstituted or substituted with one to three R¹ substituents;

wherein

each m is independently an integer from 0 to 6;

each n is independently an integer from 0 to 6

each p is independently an integer from 0 to 2;

each r is independently an integer from 1 to 3;

each s is independently an integer from 0 to 3;

each t is independently an integer from 0 to 3; and

v is independently an integer from 0 to 6;

and the pharmaceutically acceptable salts thereof.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

The present invention also relates to methods for making thepharmaceutical compositions of the present invention.

The present invention also relates to methods for eliciting an integrinreceptor antagonizing effect in a mammal in need thereof byadministering the compounds and pharmaceutical compositions of thepresent invention.

The present invention also relates to methods for inhibiting boneresorption, restenosis, atherosclerosis, inflammation, viral disease,diabetic retinopathy, macular degeneration, angiogenesis, wound healing,tumor growth, and metastasis by administering the compounds andpharmaceutical compositions of the present invention.

The present invention also relates to methods for treating osteoporosisby administering the compounds and pharmaceutical compositions of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds useful as integrin receptorantagonists. Representative compounds of the present invention aredescribed by the following chemical formula: ##STR3## wherein W isselected from the group consisting of ##STR4## a 5- or 6-memberedmonocyclic aromatic or nonaromatic ring system having 0, 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O, and S whereinthe ring nitrogen atoms are unsubstituted or substituted with one Rlsubstituent and the ring carbon atoms are unsubstituted or substitutedwith one or two R¹ substituents, and

a 9- to 14-membered polycyclic ring system, wherein one or more of therings is aromatic, and wherein the polycyclic ring system has 0, 1, 2, 3or 4 heteroatoms selected from the group consisting of N, O and S, andwherein the ring nitrogen atoms are unsubstituted or substituted withone R¹ substituent and the ring carbon atoms are unsubstituted orsubstituted with one or two R¹ substituents;

X is selected from the group consisting of

--(CH₂)_(v) --, wherein any methylene (CH₂) carbon atom is eitherunsubstituted or substituted with one or two R¹ substitutents; and a 5-or 6-membered monocyclic aromatic or nonaromatic ring system having 0,1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, andS wherein the ring nitrogen atoms are unsubstituted or substituted withone R¹ substituent and the ring carbon atoms are unsubstituted orsubstituted with one or two R¹ substituents;

Y is selected from the group consisting of

--(CH₂)_(m) --;

--(CH₂)_(m) --O--(CH₂)_(n) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --,

--(CH₂)_(m) --S--(CH₂)_(n) --,

--(CH₂)_(m) --SO--(CH₂)_(n) --,

--(CH₂)_(m) --SO₂ --(CH₂)_(n) --,

--(CH₂)_(m) --O--(CH₂)_(n) --O--(CH₂)_(p) --

--(CH₂)_(m) --O--(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,

--(CH₂)_(m) --O--(CH₂)_(n) --S--(CH₂)_(p) --,

--(CH₂)_(m) --S--(CH₂)_(n) --S--(CH₂)_(p) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --S--(CH₂)--,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --O--(CH₂)_(p) --,

--(CH₂)_(m) --S--(CH₂)_(n) --O--(CH₂)_(p) --, and

--(CH₂)_(m) --S--(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,

wherein any methylene (CH₂) carbon atom in Y, other than in R⁴, can besubstituted by one or two R³ substituents;

Z is a 5 membered aromatic or nonaromatic mono- or bicyclic ring systemhaving 0 to 3 heteroatoms selected from the group consisting of N, O,and S, and wherein the ring system is either unsubstituted orsubstituted with 0, 1, 2, or 3 oxo or thio substituents, and eitherunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of R¹⁰, R¹¹ and R¹² ;

wherein R¹ and R² are each independently selected from the groupconsisting of

hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl,C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆ alkyl, aryl, arylC₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈alkyl, (C₁₋₆ alkyl)_(p) amino, (C₁₋₆ alkyl)_(p) amino C₁₋₈ alkyl, C₁₋₄alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl,hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, C₁₋₆alkyloxy-C₁₋₆ alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,trifluoroethoxy, C₁₋₈ alkyl-S(O)_(p), (C₁₋₈ alkyl)_(p) aminocarbonyl,C₁₋₈ alkyloxycarbonylamino, (C₁₋₈ alkyl)_(p) aminocarbonyloxy, (arylC₁₋₈ alkyl)_(p) amino, (aryl)_(p) amino, aryl C₁₋₈ alkylsulfonylamino,and C₁₋₈ alkylsulfonylamino;

or two R¹ substituents, when on the same carbon atom, are taken togetherwith the carbon atom to which they are attached to form a carbonylgroup;

each R³ is independently selected from the group consisting of

hydrogen,

aryl,

C₁₋₁₀ alkyl,

aryl--(CH₂)_(r) --O--(CH₂)_(s) --,

aryl--(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) C(O)--N(R⁴)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,

halogen,

hydroxyl,

oxo,

trifluoromethyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

(C₁₋₆ alkyl)_(p) amino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ -alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl;

or two R³ substituents, when on the same carbon atom are taken togetherwith the carbon atom to which they are attached to form a carbonyl groupor a cyclopropyl group,

wherein any of the alkyl groups of R³ are either unsubstituted orsubstituted with one to three R¹ substituents, and provided that each R³is selected such that in the resultant compound the carbon atom or atomsto which R³ is attached is itself attached to no more than oneheteroatom;

each R⁴ is independently selected from the group consisting of

hydrogen,

aryl,

aminocarbonyl,

C₃₋₈ cycloalkyl,

amino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl,

(aryl C₁₋₅ alkyl)_(p) aminocarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

C₁₋₈ alkyl,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

aminosulfonyl,

C₁₋₈ alkylaminosulfonyl,

(aryl)_(p) aminosulfonyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonyl,

arylsulfonyl,

aryl C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylthiocarbonyl,

arylthiocarbonyl, and

aryl C₁₋₆ alkylthiocarbonyl,

wherein any of the alkyl groups of R⁴ are either unsubstituted orsubstituted with one to three R¹ substituents;

R⁵ and R⁶ are each independently selected from the group consisting of

hydrogen,

C₁₋₁₀ alkyl,

aryl,

aryl--(CH₂)_(r) --O--(CH₂)_(s) --,

aryl--(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --,

aryl--(CH₂)_(r) C--(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

(C₁₋₆ alkyl)_(p) amino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH=CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

or R⁵ and R⁶ are taken together with the carbon atom to which they areattached to form a carbonyl group,

wherein any of the alkyl groups of R⁵ or R⁶ are either unsubstituted orsubstituted with one to three R¹ substituents, and provided that each R⁵and R⁶ are selected such that in the resultant compound the carbon atomto which R⁵ and R⁶ are attached is itself attached to no more than oneheteroatom;

R⁷ and R⁸ are each independently selected from the group consisting of

hydrogen,

C₁₋₁₀ alkyl,

aryl,

aryl--(CH₂)_(r) --O--(CH₂)_(s) --,

aryl--(CH₂)_(r) --S(O)_(p) --(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --)

aryl--(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,

halogen,

hydroxyl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

C₃₋₈ cycloalkyl,

(C₁₋₆ alkyl)_(p) amino,

amino C₁₋₆ alkyl,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl,

aminocarbonyl C₁₋₆ alkyl,

hydroxycarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C--(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonyl amino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl, and

C₇₋₂₀ polycyclyl C₀₋₈ alkylsulfonylamino;

wherein any of the alkyl groups of R⁷ and R⁸ are either unsubstituted orsubstituted with one to three R¹ substituents, and provided that each R⁷and R⁸ are selected such that in the resultant compound the carbon atomat which R⁷ and R⁸ are attached is itself attached to no more than oneheteroatom;

R⁹ is selected from the group consisting of

hydrogen,

C₁₋₈ alkyl,

aryl,

aryl C₁₋₈ alkyl,

C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

C₁₋₈ alkylaminocarbonylmethylene, and

C₁₋₈ dialkylaminocarbonylmethylene;

R¹⁰, R¹¹ and R¹² are each independently selected from the groupconsisting of

hydrogen,

C₁₋₈ alkyl,

aryl,

halogen,

hydroxyl,

aminocarbonyl,

C₃₋₈ cycloalkyl,

amino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl,

hydroxycarbonyl,

(aryl C₁₋₅ alkyl)_(p) aminocarbonyl,

hydroxycarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkyl,

(C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,

C₁₋₈ alkylsulfonyl,

C₁₋₈ alkoxycarbonyl,

aryloxycarbonyl,

aryl C₁₋₈ alkoxycarbonyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

aminosulfonyl,

C₁₋₈ alkylaminosulfonyl,

(aryl)_(p) aminosulfonyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonyl,

C₁₋₆ alkylsulfonyl,

arylsulfonyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylthiocarbonyl,

arylthiocarbonyl,

aryl C₁₋₆ alkylthiocarbonyl,

aryl--(CH₂)_(r) --O--(CH₂)_(s) --,

aryl--(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --Y

aryl--(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --,

aryl--(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,

HC.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkyl-C.tbd.C--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-C.tbd.C---(CH₂)_(t) --,

aryl-C.tbd.C--(CH₂)_(t) --,

C₁₋₆ alkylaryl-C.tbd.C--(CH₂)_(t) --,

CH₂ ═CH--(CH₂)_(t) --,

C₁₋₁₆ alkyl-CH═CH--(CH₂)_(t) --,

C₃₋₇ cycloalkyl-CH═CH--(CH₂)_(t) --,

aryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkylaryl-CH═CH--(CH₂)_(t) --,

C₁₋₆ alkyl-SO₂ --(CH₂)_(t) --,

C₁₋₆ alkylaryl-SO₂ --(CH₂)_(t) --,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₅ alkoxy,

C₁₋₅ alkoxycarbonyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl,

C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) amino,

aminocarbonyl C₁₋₆ alkyl,

C₁₋₆ alkoxy,

aryl C₁₋₆ alkoxy,

(aryl)_(p) amino,

(aryl)_(p) amino C₁₋₆ alkyl,

(aryl C₁₋₆ alkyl)_(p) amino,

(aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,

arylcarbonyloxy,

aryl C₁₋₆ alkylcarbonyloxy,

(C₁₋₆ alkyl)_(p) aminocarbonyloxy,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

arylsulfonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

arylcarbonyl C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonyl,

aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino,

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl)_(p) aminocarbonyl C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and

(aryl C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl,

wherein any of the alkyl groups of R¹⁰, R¹¹, and R¹² are eitherunsubstituted or substituted with one to three R¹ substituents;

wherein

each m is independently an integer from 0 to 6;

each n is independently an integer from 0 to 6

each p is independently an integer from 0 to 2;

each r is independently an integer from 1 to 3;

each s is independently an integer from 0 to 3;

each t is independently an integer from 0 to 3; and

v is independently an integer from 0 to 6;

and the pharmaceutically acceptable salts thereof.

In the compounds of the present invention, W is preferably a 6-memberedmonocyclic aromatic or nonaromatic ring system having 1 or 2 nitrogenatoms wherein each carbon atom is either unsubstituted or substitutedwith one R¹ substituent, or

a 9- to 14-membered polycyclic ring system, wherein one or more of therings is aromatic, and wherein the polycyclic ring system has 0, 1, 2, 3or 4 heteroatoms selected from the group consisting of N, O, and Swherein the ring nitrogen atoms are unsubstituted or substituted withone R¹ substituent and the ring carbon atoms are uisubstituted orsubstituted with one or two R¹ substituents.

More preferably, W is selected from the group consisting of ##STR5##

Most preferably W is ##STR6##

In the compounds of the present invention, X is preferably --(CH₂)_(v)--, wherein any methylene (CH₂) carbon atom is either unsubstituted orsubstituted with one or two R¹ substituents.

More preferably X is a direct bond, that is, v is 0.

In the compounds of the present invention, Y is preferably selected fromthe group consisting of

--(CH₂)_(m) --,

--(CH₂)_(m) --O--(CH₂)_(n) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --,

--(CH₂)_(m) --S--(CH₂)_(n) --,

--(CH₂)_(m) --SO--(CH₂)_(n) --,

--(CH₂)_(m) --So2--(CH₂)_(n) --,

--(CH₂)_(m) --O--(CH₂)_(n) --O--(CH₂)_(p) --,

--(CH₂)_(m) --O--(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --NR⁴ --(CH₂)_(p) --, and

--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --O--(CH₂)_(p) --,

wherein any carbon atom in Y, other than in R⁴, can be substituted byone or two R³ substituents.

More preferably Y is selected from the group consisting of

(CH₂)_(m), (CH₂)_(m) --S--(CH₂)_(n), and (CH₂)_(m) --NR⁴ --(CH₂)_(n),

wherein any methylene (CH₂) carbon atom in Y, other than in R⁴, can besubstituted by one or two R³ substituents.

In the compounds of the present invention, Z is preferably selected fromthe group consisting of ##STR7##

More preferably Z is selected from the group consisting of ##STR8##

Most preferably Z is ##STR9##

In the compounds of the present invention, R¹ and R² are preferablyselected from the group consisting of hydrogen, halogen, C₁₋₁₀ alkyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl, hydroxy, nitro, cyano,trifluoromethyl, and trifluoromethoxy.

More preferably, R¹ and R² are selected from the group consisting ofhydrogen, halogen, C₁ -C₁₀ alkyl, C₃₋₈ cycloalkyl, trifluoromethyl, andtrifluoromethoxy.

In the compounds of the present invention, R³ is preferably selectedfrom the group consisting of

hydrogen,

fluoro,

trifluoromethyl,

aryl,

C₁₋₈ alkyl,

arylC₁₋₆ alkyl

hydroxyl,

oxo,

arylaminocarbonyl,

aryl C₁₋₅ alkylaminocarbonyl,

aminocarbonyl, and

aminocarbonyl C₁₋₆ alkyl.

More preferably, R³ is selected from the group consisting of

fluoro,

aryl,

C₁₋₈ alkyl,

aryl C₁₋₆ alkyl

hydroxyl,

oxo, and

arylaminocarbonyl.

In the compounds of the present invention, R⁴ is preferably selectedfrom the group consisting of

hydrogen,

aryl,

C₃₋₈ cycloalkyl,

C₁₋₈ alkyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

C₁₋₆ alkylsulfonyl,

arylsulfonyl,

aryl C₁₋₆ alkylsulfonyl,

aryl C₁₋₆ alkylcarbonyl,

C₁₋₈ alkylaminocarbonyl,

aryl C₁₋₆ alkylaminocarbonyl,

aryl C₁₋₈ alkoxycarbonyl, and

C₁₋₈ alkoxycarbonyl.

More preferably, R⁴ is selected from the group consisting of

hydrogen,

C₁₋₈ alkyl,

C₁₋₈ alkylcarbonyl,

arylcarbonyl,

aryl C₁₋₆ alkylcarbonyl,

C₁₋₆ alkylsulfonyl,

arylsulfonyl, and

aryl C₁₋₆ alkylsulfonyl.

In one embodiment of the present invention, R⁵ and R⁶ are eachindependently selected from the group consisting of

hydrogen,

aryl,

C₁₋₈ alkyl,

aryl-C.tbd.C--(CH₂)_(t) --,

aryl C₁₋₆ alkyl,

CH₂ ═CH--(CH₂)_(t) --, and

HC.tbd.C--(CH₂)_(t) --.

In a class of this embodiment of the present invention, R⁶ is hydrogenand R⁵ is selected from the group consisting of

hydrogen,

aryl,

C₁₋₈ alkyl,

aryl-C.tbd.C--(CH₂)_(t) --,

aryl C₁₋₆ alkyl,

CH₂ ═CH--(CH₂)_(t) --, and

HC.tbd.C--(CH₂)_(t) --.

In a subclass of this class of the present invention, R⁶, R⁷, and R⁸ areeach hydrogen and R⁵ is selected from the group consisting of

hydrogen,

aryl,

C₁₋₈ alkyl,

aryl-C.tbd.C-(CH₂)_(t) --,

aryl C₁₋₆ alkyl,

CH₂ ═CH--(CH₂)_(t) --, and

HC.tbd.C--(CH₂)_(t) --.

In another embodiment of the present invention, R⁷ and R⁸ are eachindependently selected from the group consisting of

hydrogen,

aryl,

C₁₋₈ alkylcarbonylamino,

arylcarbonylamino,

C₁₋₈ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

arylsulfonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

C₁₋₈ alkoxycarbonylamino,

C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

aryloxycarbonylamino C₁₋₈ alkyl,

aryl C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

arylcarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

aminocarbonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl)_(p) aminocarbonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl,

aminosulfonylamino C₁₋₆ alkyl,

(C₁₋₈ alkyl)_(p) aminosulfonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino,

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino,

C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

arylthiocarbonylamino C₁₋₆ alkyl,

aryl C₁₋₆ alkylthiocarbonylamino, and

aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl.

In a class of this embodiment of the present invention, R⁸ is hydrogenand R⁷ is selected from the group consisting of consisting of

hydrogen,

aryl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino,

arylcarbonylamino,

C₁₋₈ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino,

arylaminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino, and

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino.

In a subclass of this class of the present invention, R⁵, R⁶, and R⁸ areeach hydrogen and R⁷ is selected from the group consisting of

hydrogen,

aryl,

C₁₋₈ alkylcarbonylamino,

aryl C₁₋₆ alkylcarbonylamino,

arylcarbonylamino,

C₁₋₈ alkylsulfonylamino,

aryl C₁₋₆ alkylsulfonylamino,

arylsulfonylamino,

C₁₋₈ alkoxycarbonylamino,

aryl C₁₋₈ alkoxycarbonylamino,

arylaminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminocarbonylamino,

(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,

(C₁₋₈ alkyl)_(p) aminosulfonylamino, and

(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino.

In the compounds of the present invention, R⁹ is preferably selectedfrom the group consisting of hydrogen, methyl, and ethyl.

More preferably, R⁹ is hydrogen.

In the compounds of the present invention, R¹⁰, R¹¹, and R¹² arepreferably each independently selected from the group consisting ofhydrogen and C₁₋₈ alkyl. More preferably R¹⁰, R¹¹, and R¹² are hydrogen.

In the compounds of the present invention, m is preferably an integerfrom 0 to 4, more preferably from 0 to 3.

In the compounds of the present invention, n is preferably an integerfrom 0 to 4, more preferably from 0 to 3.

In the compounds of the present invention, r is preferably an integerfrom 1 to 2.

In the compounds of the present invention, s is preferably an integerfrom 0 to 2.

In the compounds of the present invention, t is preferably an integerfrom 0 to 2, more preferably from 0 to 1.

In the compounds of the present invention, v is preferably 0.

In certain embodiments of the present invention the compounds have theformula with the following designated stereochemistry: ##STR10## whereinthe substituents W, X, Y, Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, and R¹², and the subscripts m, n, p, r, s, t, and v are asdescribed above.

Illustrative but nonlimiting examples of compounds of the presentinvention that are useful as integrin receptor antagonists are thefollowing:

Ethyl3(S)-(3-fluorophenyl)-3-[2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionate;

Ethyl3(S)-(3-fluorophenyl)-3-[2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionate;

Ethyl3(S)-(2,3-dihydro-benzofuran-6-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate;

Ethyl3(S)-(2,3-dihydro-benzofuran-6-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate;

Ethyl3(S)-(quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate;

Ethyl3(S)-(quinolin-3-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate;

3(S)-(3-Fluorophenyl)-3-[2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionicacid;

3(S)-(3-Fluorophenyl)-3-[2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionicacid;

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(Quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(Quinolin-3-yl)-3-(2-oxo(S)-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

2(S)-Benzenesulfonylamino-3-[3-(3-[1,8]naphthyridin-2-yl-propyl)-[1,2,4]oxadiazol-5-yl]-propionicacid;

3(S)-(6-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(6-Amino-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(4-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid;

3-(6-Methylamino-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(2-Fluoro-biphenyl-4-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(2-Oxo-2,3-dihydro-benzoxazol-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(4-Ethoxry-3-fluorophenyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(5-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(5-Methoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(Ethynyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(6-Methoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(2-Oxo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(2,3-Dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(2-Oxo-3,4-dihydro-2H-1-oxa-4,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacdd;

3(S-(3,4-Dihydro-2H-1-oxa-4,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3-(Furo-[2,3-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3-(2,3-Dihydrofuro[2,3-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3-(Furo-[3,2-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3-(2,3-Dihydrofuro[3,2-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid;

3(S)-(Benzimidazol-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(1H-Imidazo[4,5-c]pyridin-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(Benzoxazol-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(1-Methyl-1H-pyrazol-4-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl}-pent-4-enoicacid; and the pharmaceutically acceptable salts thereof.

Further illustrative of the present invention are compounds selectedfrom the group consisting of

3(S)-(3-Fluorophenyl)-3-[2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionicacid;

3(S)-(3-Fluorophenyl)-3-[2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionicacid;

3(S-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(R-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid;

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(Quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(Quinolin-³-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

and the pharmaceutically acceptable salts thereof

For use in medicine, the salts of the compounds of this invention referto non-toxic "pharmaceutically acceptable salts." Other salts may,however, be useful in the preparation of the compounds according to theinvention or of their pharmaceutically acceptable salts. Saltsencompassed within the term "pharmaceutically acceptable salts" refer tonon-toxic salts of the compounds of this invention which are generallyprepared by reacting the free base with a suitable organic or inorganicacid. Representative salts include the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts.

The compounds of the present invention can have chiral centers and occuras racemates, racemic mixtures, diastereomeric mixtures, and asindividual diastereomers, or enantiomers with all isomeric forms beingincluded in the present invention. Therefore, where a compound ischiral, the separate enantiomers or diastereomers, substantially free ofthe other, are included within the scope of the invention; furtherincluded are all mixtures of the two enantiomers. Also included withinthe scope of the invention are polymorphs and hydrates of the compoundsof the instant invention.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befinctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the term "administering"shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation. of suitable prodrug derivatives aredescribed, for example, in "Design of Prodrugs," ed. H. Bundgaard,Elsevier, 1985, which is incorporated by reference herein in itsentirety. Metabolites of these compounds include active species producedupon introduction of compounds of this invention into the biologicalmilieu.

The term "therapeutically effective amount" shall mean that amount of adrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought by aresearcher or clinician.

The term "integrin receptor antagonist," as used herein, refers to acompound which binds to and antagonizes either the ανβ3 receptor, theανβ5 receptor, or the ανβ6 receptor, or a compound which binds to andantagonizes combinations of these receptors (for example, a dualανβ3/ανβ5 receptor antagonist).

The term "bone resorption," as used herein, refers to the process bywhich osteoclasts degrade bone.

The term "alkyl" shall mean straight or branched chain alkanes of one toten total carbon atoms, or any number within this range (i.e., methyl,ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).

The term "alkenyl" shall mean straight or branched chain alkenes of twoto ten total carbon atoms, or any number within this range.

The term "alkynyl" shall mean straight or branched chain alkynes of twoto ten total carbon atoms, or any number within this range.

The term "cycloalkyl" shall mean cyclic rings of alkanes of three toeight total carbon atoms, or any number within this range (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl).

The term "cycloheteroalkyl," as used herein, shall mean a 3- to8-membered fully saturated heterocyclic ring containing one or twoheteroatoms chosen from N, O or S. Examples of cycloheteroalkyl groupsinclude, but are not limited to piperidinyl, pyrrolidinyl, azetidinyl,morpholinyl, piperazinyl.

The term "alkoxy," as used herein, refers to straight or branched chainalkoxides of the number of carbon atoms specified (e.g., C₁₋₅ alkoxy),or any number within this range (i.e., methoxy, ethoxy, etc.).

The term "aryl," as used herein, refers to a monocyclic or polycyclicsystem comprising at least one aromatic ring, wherein the monocylic orpolycyclic system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N,O, or S, and wherein the monocylic or polycylic system is eitherunsubstituted or substituted with one or more groups independentlyselected from hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, aryl,aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino, C₁₋₃ acylaminoC₁₋₈ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkylamino C₁₋₈ alkyl, C₁₋₆dialkylamino, C₁₋₆ dialkylamino-C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxyC₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl, C₁₋₅alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl, hydroxycarbonyl C₁₋₆alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, cyano, trifluoromethyl, oxo or Cl5 alkylcarbonyloxy. Examples of aryl include, but are not limited to,phenyl, naphthyl, pyridyl, pyrryl, pyrazolyl, pyrazinyl, pyrimidinyl,imidazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl,thienyl, furyl, dihydrobenzofuryl, benzo(1,3) dioxolane, oxazolyl,isoxazolyl and thiazolyl, which are either unsubstituted or substitutedwith one or more groups independently selected from hydrogen, halogen,C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈ alkyl, C₁₋₆ alkylamino, C₁₋₆alkylamino-C₁₋₈ alkyl, C₁₋₆ dialkylamino, C₁₋₆ dialkylamino C₁₋₈ alkyl,C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonylC₁₋₆ alkyl, C₁₋₅ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl,hydroxycarbonyl C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, cyano,trifluoromethyl, oxo or C₁₋₅ alkylcarbonyloxy. Preferably, the arylgroup is unsubstituted, mono-, di-, tri- or tetra-substituted with oneto four of the above-named substituents; more preferably, the aryl groupis unsubstituted, mono-, di- or tri-substituted with one to three of theabove-named substituents; most preferably, the aryl group isunsubstituted, mono- or di-substituted with one to two of theabove-named substituents.

Whenever the term "alkyl" or "aryl" or either of their prefix rootsappear in a name of a substituent (e.g., aryl C₀₋₈ alkyl) it shall beinterpreted as including those limitations given above for "alkyl" and"aryl." Designated numbers of carbon atoms (e.g., C₁₋₁₀) shall referindependently to the number of carbon atoms in an alkyl or cyclic alkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

The terms "arylalkyl" and "alkylaryl" include an alkyl portion wherealkyl is as defined above and to include an aryl portion where aryl isas defined above. Examples of arylalkyl include, but are not limited to,benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl,fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, andthienylpropyl. Examples of alkylaryl include, but are not limited to,toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine,propylpyridine and butylpyridine.

In the compounds of the present invention, two R¹ substituents, when onthe same carbon atom, can be taken together with the carbon to whichthey are attached to form a carbonyl group.

In the compounds of the present invention, two R³ substituents, when onthe same carbon atom, can be taken together with the carbon atom towhich they are attached to form a carbonyl group. In such instances, thelimitation, that in the resultant compound the carbon atom or atoms towhich R³ is attached is itself attached to no more than one heteroatom,does not apply. Also, in the compounds of the present invention, two R³substituents, when on the same carbon atom, can be taken together withthe carbon atom to which they are attached to form a cyclopropyl group.

In the compounds of the present invention, R⁵ and R⁶ can be takentogether with the carbon atom to which they are attached to form acarbonyl group. In such instances, the limitation, that in the resultantcompound the carbon atom to which R⁵ and R⁶ is attached is itselfattached to no more than one heteroatom, does not apply.

The term "halogen" shall include iodine, bromine, chlorine, andfluorine.

The term "oxy" means an oxygen (O) atom. The term "thio" means a sulfur(S) atom. The term "oxo" means "═O". The term "carbonyl" means "C═O."

The term "substituted" shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

Under standard nonmenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent finctionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to ##STR11##

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. W, X, Y, Z,R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹², and thesubscripts m, n, p, r, s, t and v are to be chosen in conformity withwell-known principles of chemical structure connectivity.

Representative compounds of the present invention typically displaysubmicromolar affinity for the integrin receptors, particularly theανβ3, ανβ5, and/or ανβ6 receptors. Compounds of this invention aretherefore useful for treating mammals suffering from a bone conditioncaused or mediated by increased bone resorption, who are in need of suchtherapy. Pharmacologically effective amounts of the compounds, includingpharamaceutically acceptable salts thereof, are administered to themammal, to inhibit the activity of mammalian osteoclasts.

The compounds of the present invention are administered in dosageseffective to antagonize the ανβ3 receptor where such treatment isneeded, as, for example, in the prevention or treatment of osteoporosis.

Further exemplifying the invention is the method wherein the integrinreceptor antagonizing effect is an ανβ3 antagonizing effect.

An illustration of the invention is the method wherein the ανβ3antagonizing effect is selected from inhibition of bone resorption,restenosis, angiogenesis, diabetic retinopathy, macular degeneration,inflammation, viral disease, tumor growth, or metastasis. Preferably,the (ανβ3 antagonizing effect is the inhibition of bone resorption.

An example of the invention is the method wherein the integrin receptorantagonizing effect is an ανβ5 antagonizing effect. More specifically,the ανβ5 antagonizing effect is selected from inhibition of: restenosis,angiogenesis, diabetic retinopathy, macular degeneration, inflammation,tumor growth, or metastasis.

Illustrating the invention is the method wherein the integrin receptorantagonizing effect is a dual ανβ3/ανβ5 antagonizing effect. Morepafticularly, the dual ανβ3/ανβ5 antagonizing effect is selected frominhibition of bone resorption, restenosis, angiogenesis, diabeticretinopathy, macular degeneration, inflammation, viral disease, tumorgrowth, or metastasis.

Illustrating the invention is the method wherein the integrin receptorantagonizing effect is an ανβ6 antagonizing effect. More particularly,the ανβ6 antagonizing effect is selected from inhibition ofangiogenesis, inflammatory response, or wound healing.

Illustrating the invention is the method wherein the ανβ3 antagonizingeffect is selected from inhibition of bone resorption, inhibition ofrestenosis, inhibition of angiogenesis, inhibition of diabeticretinopathy, inhibition of macular degeneration, inhibition ofatherosclerosis, inflammation, viral disease, or inhibition of tumorgrowth or metastasis. Preferably, the ανβ3 antagonizing effect is theinhibition of bone resorption.

More particularly illustrating the invention is a pharmaceuticalcomposition comprising any of the compounds described above and apharmaceutically acceptable carrier. Another example of the invention isa pharmaceutical composition made by combining any of the compoundsdescribed above and a pharmaceutically acceptable carrier. Anotherillustration of the invention is a process for making a pharmaceuticalcomposition comprising combining any of the compounds described aboveand a pharmaceutically acceptable carrier.

Further illustrating the invention is a method of treating and/orpreventing a condition mediated by antagonism of an integrin receptor ina mammal in need thereof, comprising administering to the mammal atherapeutically effective amount of any of the compounds describedabove. Preferably, the condition is selected from bone resorption,osteoporosis, restenosis, diabetic retinopathy, macular degeneration,angiogenesis, atherosclerosis, inflammation, viral disease, cancer,tumor growth, and metastasis. More preferably, the condition is selectedfrom osteoporosis and cancer. Most preferably, the condition isosteoporosis.

More specifically exemplifying the invention is a method of eliciting anintegrin antagonizing effect in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of any ofthe compounds or any of the pharmaceutical compositions described above.Preferably, the integrin antagonizing effect is an ανβ3 antagonizingeffect; more specifically, the ανβ3 antagonizing effect is selected frominhibition of bone resorption, inhibition of restenosis, inhibition ofatherosclerosis, inhibition of angiogenesis, inhibition of diabeticretinopathy, inhibition of macular degeneration, inhibition ofinflammation, inhibition of viral disease, or inhibition of tumor growthor metastasis. Most preferably, the (ανβ3 antagonizing effect isinhibition of bone resorption. Alternatively, the integrin antagonizingeffect is an ανβ5 antagonizing effect, an ανβ6 antagonizing effect, or amixed ανβ3, ανβ5, and ανβ6 antagonizing effect. Examples of ανβ5antagonizing effects are inhibition of restenosis, atherosclerosis,angiogenesis, diabetic retinopathy, macular degeneration, inflammation,viral disease, or tumor growth. Examples of dual ανβ6 antagonizingeffects are inhibition of angiogenesis, inflammatory response and woundhealing.

Additional examples of the invention are methods of inhibiting boneresorption and of treating and/or preventing osteoporosis in a mammal inneed thereof, comprising administering to the mammal a therapeuticallyeffective amount of any of the compounds or any of the pharmaceuticalcompositions described above.

Additional illustrations of the invention are methods of treatinghypercalcemia of malignancy, osteopenia due to bone metastases,periodontal disease, hyperparathyroidism, periarticular erosions inrheumatoid arthritis, Paget's disease, immobilization-inducedosteopenia, and glucocorticoid treatment in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of any of the compounds or any of the pharmaceutical compositionsdescribed above.

More particularly exemplifying the invention is the use of any of thecompounds described above in the preparation of a medicament for thetreatment and/or prevention of osteoporosis in a mammal in need thereofStill further exemplifying the invention is the use of any of thecompounds described above in the preparation of a medicament for thetreatment and/or prevention of bone resorption, tumor growth, cancer,restenosis, atherosclerosis, diabetic retinopathy, macular degeneration,inflammation, viral disease, and/or angiogenesis.

Also exemplifying the invention are compositions further comprising anactive ingredient selected from the group consisting of

a.) an organic bisphosphonate or a pharmaceutically acceptable salt orester thereof,

b.) an estrogen receptor modulator,

c.) a cytotoxic/antiproliferative agent,

d.) a matrix metalloproteinase inhibitor,

e.) an inhibitor of epidermal-derived, fibroblast-derived, orplatelet-derived growth factors,

f.) an inhibitor of VEGF,

g.) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1,

h.) a cathepsin K inhibitor, and

i.) a prenylation inhibitor, such as a farnesyl transferase inhibitor ora geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyltransferase inhibitor; and mixtures thereof.

(See, B. Millauer et al., "Dominant-Negative Inhibition of Flk-1Suppresses the Growth of Many Tumor Types in Vivo", Cancer Research, 56,1615-1620 (1996), which is incorporated by reference herein in itsentirety).

Preferably, the active ingredient is selected from the group consistingof:

a.) an organic bisphosphonate or a pharmaceutically acceptable salt orester thereof,

b.) an estrogen receptor modulator, and

c.) a cathepsin K inhibitor; and mixtures thereof.

Nonlimiting examples of such bisphosphonates include alendronate,etidronate, pamidronate, risedronate, ibandronate, and pharmaceuticallyacceptable salts and esters thereof. A particularly preferredbisphosphonate is alendronate, especially alendronate monosodiumtrihydrate.

Nonlimiting examples of estrogen receptor modulators include estrogen,progesterin, estradiol, droloxifene, raloxifene, and tamoxifene.

Nonlimiting examples of cytotoxic/antiproliferative agents are taxol,vincristine, vinblastine, and doxorubicin.

Cathepsin K, formerly known as cathepsin O2, is a cysteine protease andis described in PCT International Application Publication No. WO96/13523, published May 9, 1996; U.S. Pat. No. 5,501,969, issued Mar. 3,1996; and U.S. Pat. No. 5,736,357, issued Apr. 7, 1998, all of which areincorporated by reference herein in their entirety. Cysteine proteases,specifically cathepsins, are linked to a number of disease conditions,such as tumor metastasis, inflammation, arthritis, and bone remodeling.At acidic pH's, cathepsins can degrade type-I collagen. Cathepsinprotease inhibitors can inhibit osteoclastic bone resorption byinhibiting the degradation of collagen fibers and are thus useful in thetreatment of bone resorption diseases, such as osteoporosis.

The present invention is also directed to combinations of the compoundsof the present invention with one or more agents useful in theprevention or treatment of osteoporosis. For example, the compounds ofthe instant invention may be effectively administered in combinationwith effective amounts of other agents such as an organicbisphosphonate, an estrogen receptor modulator, or a cathepsin Kinhibitor.

Additional illustrations of the invention are methods of treating tumorgrowth in a mammal in need thereof, comprising administering to themammal a therapeutically effective amount of a compound described aboveand one or more agents known to be cytotoxic/antiproliferative. Also,the compounds of the present invention can be administered incombination with radiation therapy for treating tumor growth andmetastasis.

In addition, the integrin ανβ3 antagonist compounds of the presentinvention may be effectively administered in combination with a growthhormone secretagogue in the therapeutic or prophylactic treatment ofdisorders in calcium or phosphate metabolism and associated diseases.These diseases include conditions which can benefit from a reduction inbone resorption. A reduction in bone resorption should improve thebalance between resorption and formation, reduce bone loss or result inbone augmentation. A reduction in bone resorption can alleviate the painassociated with osteolytic lesions and reduce the incidence and/orgrowth of those lesions. These diseases include: osteoporosis (includingestrogen deficiency, immobilization, glucocorticoid induced and senile),osteodystrophy, Paget's disease, myositis ossificans, Bechterew'sdisease, malignant hypercalcemia, metastatic bone disease, periodontaldisease, cholelithiasis, nephrolithiasis urolithiasis, urinary calculus,hardening of the arteries (sclerosis), arthritis, bursitis, neuritis andtetany. Increased bone resorption can be accompanied by pathologicallyhigh calcium and phosphate concentrations in the plasma, which would bealleviated by this treatment. Similarly, the present invention would beuseful in increasing bone mass in patients with growth hormonedeficiency. Thus, preferred combinations are simultaneous or alternatingtreatments of an ανβ3 receptor antagonist of the present invention and agrowth hormone secretagogue, optionally including a third componentcomprising an organic bisphosphonate, preferably alendronate monosodiumtrihydrate.

In accordance with the method of the present invention, the individualcomponents of the combination can be administered separately atdifferent times during the course of therapy or concurrently in dividedor single combination forms. The instant invention is therefore to beunderstood as embracing all such regimes of simultaneous or alternatingtreatment, and the term "administering" is to be interpretedaccordingly. It will be understood that the scope of combinations of thecompounds of this invention with other agents useful for treatingintegrin-mediated conditions includes in principle any combination withany pharmaceutical composition useful for treating osteoporosis.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, topical (e.g., ocular eyedrop), subcutaneous,intramuscular or transdermal (e.g., patch) form, all using forms wellknown to those of ordinary skill in the pharmaceutical arts. Aneffective but non-toxic amount of the compound desired can be employedas an ανβ3 antagonist.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic finction of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician,veterinarian or clinician can readily determine and prescribe theeffective amount of the drug required to prevent, counter or arrest theprogress of the condition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.01 mg per kg of body weight per day(mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, andmost preferably 0.1 to 5.0 mg/kg/day. For oral administration, thecompositions are preferably provided in the form of tablets containing0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. A medicament typically containsfrom about 0.01 mg to about 500 mg of the active ingredient, preferably,from about 1 mg to about 100 mg of active ingredient. Intravenously, themost preferred doses will range from about 0.1 to about 10 mg/kg/minuteduring a constant rate infusion. Advantageously; compounds of thepresent invention may be administered in a single daily dose, or thetotal daily dosage may be administered in divided doses of two, three orfour times daily. Furthermore, preferred compounds for the presentinvention can be administered in intranasal form via topical use ofsuitable intranasal vehicles, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin the art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as `carrier` materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegratorsinclude, without limitation, starch, methyl cellulose, agar, bentonite,xanthan gum and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcrosslinked or amphipathic block copolymers of hydrogels.

In the schemes and examples below, various reagent symbols andabbreviations have the following meanings:

AcOH: Acetic acid.

BH₃ ·DMS: Borane·dimethylsulfide.

BOC(Boc): t-Butyloxycarbonyl.

BOP: Benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate.

CBZ(Cbz): Carbobenzyloxy or benzyloxycarbonyl.

CDI: Carbonyldiimidazole.

CH₂ Cl₂ : Methylene chloride.

CH₃ CN: Acetonitrile

CHCl₃ : Chloroform.

DEAD: Diethyl azodicarboxylate.

DIAD: Diisopropyl azodicarboxylate.

DIBAH or DIBAL-H: Diisobutylaluminum hydride.

DIPEA: Diisopropylethylamine.

DMAP: 4-Dimethylaminopyridine.

DME: 1,2-Dimethoxyethane.

DMF: Dimethylformamide.

DMSO: Dimethylsulfoxide.

DPFN: 3,5-Dimethyl-1-pyrazolylformamidine nitrate.

EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide ·HCl

EtOAc: Ethyl acetate.

EtOH: Ethanol.

HOAc: Acetic acid.

HOAT: 1-Hydroxy-7-azabenzotriazole

HOBT: 1-Hydroxybenzotriazole.

IBCF: Isobutylchloroformate

LDA: Lithium diisopropylamide.

MeOH: Methanol.

MMNG 1,1-methyl-3-nitro-1-nitrosoguanidine

NEt₃ : Triethylamine.

NMM: N-methylmorpholine.

PCA·HCl: Pyrazole carboxamidine hydrochloride.

Pd/C: Palladium on activated carbon catalyst.

Ph: Phenyl.

pTSA p-Toluenesulfonic acid.

TEA: Triethylamine.

TFA: Trifluoroacetic acid.

THF: Tetrahydrofuran.

TLC: Thin Layer Chromatography.

TMEDA: N,N,N',N'-Tetramethylethylenediamine.

TMS: Trimethylsilyl.

The novel compounds of the present invention can be prepared accordingto the procedure of the following schemes and examples, usingappropriate materials and are further exemplified by the followingspecific examples. The compounds illustrated in the examples are not,however, to be construed as forming the only genus that is considered asthe invention. The following examples further illustrate details for thepreparation of the compounds of the present invention. Those skilled inthe art will readily understand that known variations of the conditionsand processes of the following preparative procedures can be used toprepare these compounds. All temperatures are degrees Celsius unlessotherwise noted.

The following Schemes and Examples describe procedures for makingrepresentative compounds of the present invention. Moreover, byutilizing the procedures described in detail in PCT InternationalApplication Publication Nos. WO95/32710, published Dec. 7, 1995, andWO95/17397, published Jun. 29, 1995, both of which are incorporated byreference herein in their entirety, in conjunction with the disclosurecontained herein, one of ordinary skill in the art can readily prepareadditional compounds of the present invention claimed herein.Additionally, for a general review describing the synthesis ofβ-alanines which can be utilized as the C-terminus of the compounds ofthe present invention, see Cole, D. C., Recent Stereoselective SyntheticApproaces to β-Amino Acids, Tetrahedron, 1994, 50, 9517-9582; Juaristi,E, et al., Enantioselective Synthesis of β-Amino Acids, AldrichimicaActa, 1994, 27, 3. In particular, synthesis of the 3-methyl-β-alanine istaught in Duggan, M. F. et al., J. Med. Chem., 1995, 38, 3332-3341; the3-ethynyl-β-alanine is taught in Zablocki, J. A., et al., J. Med. Chem.,1995, 38, 2378-2394; the 3-(pyridin-3-yl)-β-alanine is taught in Rico,J. G. et al., J. Org. Chem., 1993, 58, 7948-7951; and the 2-amino- and2-tosylamino-β-alanines are taught in Xue, C-B, et al., Biorg. Med.Chem. Letts., 1996, 6, 339-344. The references described in thisparagraph are all also incorporated by reference herein in theirentirety. ##STR12##

Ethyl 3-fluorocinnamate (1-2)

To a solution of 3-fluorobenzaldehyde 1-1 (18.16 g, 146 mmol) indichloromethane (500 mL) was added ethyl(triphenylphosphoranylidene)acetate (61.2 g; 176 mmol), and theresulting solution was stirred at room temperature for 18 hr. Afterevaporation of the solvent, the residue was swirled with ether/hexaneand filtered. The filtrate was concentrated and then purified on a plugof silica gel eluting with hexane/EtOAc 9:1. Removal of the solventafforded the title compound 1-2 as an oil (˜95% trans) which was usedwithout further purification in the next step.

¹ H NMR(CDCl₃) δ 1.36 (3 H, t), 4.28 (2 H, q), 6.43 (1 H, d), 7.08 (1 H,m), 7.2-7.4 (3 H, m), 7.64 (1 H, d).

N-Benzyl-(R)-α-methylbenzyl-3(S)-fluorophenyl-β-alanine ethyl ester(1-3)

To a solution of N-benzyl-(R)-α-methylbenzylamine (33.4 g, 158 mmol) inTHF (450 mL) at 0° C. was added n-butyllithium (1.6M in hexanes; 99 mL,158 mmol). The dark violet solution was stirred at 0° C. for 30 minutes,cooled to -78° C., and the ester 1-2 (29.2 g, 150 mmol) in THF (100 mL)was added over 5 minutes. The resulting solution was stirred at -78° C.for 1 hr., then warmed to room temperature. After 2 hrs, the mixture waspoured into water and extracted with EtOAc, washed with water thenbrine, dried and concentrated in vacuo to give an oil. Columnchromatography (silica gel; hexane/EtOAc 1:1 then pure EtOAc) gave thetitle compound 1-3. ¹ H NMR (CDCl₃): δ 1.06 (3 H, t), 1.28 (3 H, d),2.52 (1 H, dd), 2.62 (1 H, dd), 3.66 (1 H, d), 3.72 (1 H, d), 3.95 (2 H,q), 4.44 (1 H, dd), 6.95 (1 H, m), 7.1-7.5 (13 H, m).

3(S)-Fluorophenyl-β-alanine ethyl ester hydrochloride (1-4)

A solution of the N-benzyl-(R)-α-methylbenzylamine 1-3 (28.2 g, 69.6mmol) in ethanol (300 mL), acetic acid (30 mL) and water (3 mL) wasdegassed with argon for 30 minutes. Pd(OH)₂ on carbon (20% dry weight;2.6 g) was added and the mixture then stirred under a hydrogenatmosphere (balloon) for 2 hours. The mixture was filtered throughcelite and the solvent removed in vacuo to give an oil. This oil wasdissolved in 200 mL ether and to this solution was added 60 mL 1N HCl inether to yield a precipitate. Filtration and washing the solid withether/hexane then gave the title compound 1-4 as a white solid. ¹ HNMR(CD₃ OD) δ 1.21 (3 H, t), 3.0-3.2 (2 H, m), 4.16 (2 H, q), 4.76 (1 H,t), 7.2-7.35 (3 H, m), 7.5 (1 H, m). ##STR13##

5-(2-methyl-[1,3]dioxolan-2-yl)-pentanoic acid (2-2)

A mixture of ketone 2-1 (18 g, 105 mmol), ethylene glycol (3.2 ml, 110mmol), p-TSA (50 mg, 0.2713 mmol) and toluene (300 mL) was heated toreflux with azeotropic removal of water for 24 hours. The reactionmixture was diluted with EtOAc and then washed with sat. NaHCO₃, brine,dried (MgSO₄), and concentrated. The residue was dissolved in EtOH (200ml) and then treated with 1N NaOH (120 ml, 120 mmol). After 2 h, thereaction was poured into 600 mL 2:1 Et₂ O/10% KHSO₄. The organic portionwas separated, washed with brine, dried (MgSO₄) and concentrated to giveacid 2-2 as a colorless oil.

¹ H NMR (300 MHz, CDCl₃) δ 3.93 (m, 4 H), 2.36 (m, 2 H), 1.63 (m, 4 H),1.46 (m, 2 H), 1.31 (s, 3 H).

3-[5-(2-methyl-[1,3]dioxolan-2-yl)-pentanoyl]-oxazolidin-2-one (2-3)

To a stirred solution of 2-2 (16.0 g, 85.5 mmol), NEt3 (13.1 ml, 94.1mmol) and THF (400 mL) at -78° C. was added pivaloyl chloride (11.6 ml,94.1 mmol). The mixture was warmed to 0° C. for 1.0 h and then recooledto -78° C. To a stirred solution of 2-oxazolidinone (9.3 g, 106.9 mmol)and THF (200 ml) at -78° C. was added nBuLi (43.0 ml, 106.9 mmol, 2.5Min hexanes) dropwise over 10 minutes. After 20 minutes, the lithiumreagent was transferred to the mixed anhydride via cannula. After 10minutes, the reaction was warmed to 0° C. for 1.0 h. The mixture wasdiluted with ethyl acetate, washed with sat. NaHCO₃, brine, and driedover MgSO₄. Following evaporative removal of the solvent, the residuewas chromatographed (silica gel, 40%-50% EtOAc/hexanes) to give 2-3 as acolorless foam.

TLC R_(f) =0.19 (silica, 40% EtOAc/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 4.41 (t, J=8.1 Hz, 2 H), 4.02 (t, J=8.1 Hz, 2H), 3.93 (m, 4 H ), 3.93 (t, J=7.3 Hz, 2 H), 1.66 (m, 4 H), 1.48 (m, 2H), 1.31 (s, 3 H).

3-(2-[3-(2-methyl-[1,3]dioxolan-2-yl)-propyl]-pent-4-enoyl)-oxazolidin-2-one(2-4)

To a stirred solution of 2-3 (6.0 g, 23.3 mmol) and THF (125 mL) at -78°C. was added LiN(TMS)₂ (18.9 mL, 37.8 mmol, 1.0M in THF) dropwise over10 minutes. After 20 minutes, allyl bromide was added. After 10 minutes,the reaction was warmed to 0° C. After 4.0 h, the reaction was dilutedwith EtOAc, washed with sat. NaHCO₃, brine, dried (MgSO₄) andconcentrated. Flash chromatography (silica, 50% EtOAc/hexanes) gave 2-4as an yellow oil.

TLC R_(f) =0.26 (silica, 50% EtOAc/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 5.76 (m, 1 H), 5.02 (m, 1 H), 4.40 (t, J=8.3Hz, 2 H), 4.02 (m, 2 H), 3.99 (m, 4 H), 2.39 (m, 1 H), 2.27 (m, 1 H),1.72 (m, 1 H), 1.62 (m, 2 H) 1.39-1.53 (m, 3 H), 1.30 (s, 3 H).

6-(2-methyl-[1,3]dioxolan-2-yl)-3-(2-oxo-oxazolidine-3-carbonyl)-hexanal(2-5)

To a stirred solution of 2-4 (4.0 g, 13.5 mmol), sudan III (10 mg) andCH₂ Cl₂ (350 mL) at -78° C. under argon was bubbled ozone until redsolution changed to yellow-orange. The solution was purged with argonfor 30 minutes. PPh₃ (5.28 g, 20.3 mmol) was added followed by theremoval of the cooling bath. After 3.0 h, the reaction was concentrated.Flash chromatography (silica, 20%-50% EtOAc/hexanes) gave 2-5 as ayellow oil.

TLC R_(f=) 0.15 (silica, 50% EtOAc/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 9.74 (s, 1 H), 4.43 (m, 2 H), 4.15 (m, 1 H),4.03 (m, 2 H), 3.91 (m, 4 H), 3.04 (m, 1 H), 2.67 (dd, J=3.9 Hz, 18.6Hz, lH),1.65 (m, 3 H), 1.45 (m, 3 H), 1.29 (s, 3 H).

3(S)-(3-Fluorophenyl)-3-(3-[3-(2-methyl-[1,3]dioxolan-2-yl)-propyl]-2-oxo-pyrrolidin-1-yl)-pronionicacid ethyl ester (2-6)

A mixture of 2-5 (302 mg, 1.11 mmol), 14 (300 mg, 1.21 mmol), Na(OAc)₃BH (321 mg, 1.52 mmol) and NEt₃ (0.28 mL, 2.02 mmol) in DCE (10 mL) wasstirred for 48 h. The mixture was diluted with ethyl acetate, washedwith sat. NaHCO₃, brine, and dried over MgSO₄. Following evaporativeremoval of the solvent, the residue was chromatographed (silica gel,50:35:14:1 hexanes/chloroform/ethyl acetate/ MeOH) to give 2-6 as awhite solid.

TLC R_(f) =0.41 (silica, 70:25:5 chloroform/ethyl acetate/MeOH)

¹ H NMR (300 MHz, CDCl₃) δ 7.30 (m, 1 H), 7.07 (m, 1 H), 6.98 (m 3 H),5.68 (m, 1 H), 4.12 (m, 2 H), 3.92 (m, 4 H), 3.30 (m, 1 H), 2.97 (m, 3H), 2.38 (m, 1 H), 2.14 (m, 1 H), 1.86 (m, 1 H), 1.64 (m, 4 H), 1.42 (m,2 H), 1.30 (2s, 3 H), 1.22 (t, J=7.3 Hz, 3 H).

3(S)-(3-Fluorophenyl)-3-[2-oxo-3-(4-oxo-pentyl)-pyrrolidin-1-yl]-propionicacid ethyl ester (2-7)

A solution of 2-6 (450 mg, 1.10 mmol), p-TSA (50 mg) and acetone (50 mL)was heated at reflux for 4 hr. The cooled reaction mixture was dilutedwith EtOAc and then washed with sat. NaHCO₃ and brine, dried (MgSO₄),and concentrated to afford 2-7 as a yellow solid.

¹ H NMR (300 MHz, CDCl₃) δ 7.30 (m, 1 H), 7.06 (m, 1 H), 6.98 (m, 2 H),5.67 (m, 1 H), 4.12 (m, 2 H), 3.23 (m, 1 H), 2.97 (m, 2 H), 2.33-2.49(m, 3 H), 2.14 (2s, 3 H), 1.54-1.86 (m, 5 H), 1.33 (m, 1 H), 1.22 (t,J=7.1 Hz, 3 H).

3(S)-(3-Fluorophenyl)-3-[3-(3-[1,8]naphthyridin-2-yl-propyl)-2-oxo-pyrrolidin-1-yl]-propionicacid ethyl ester (2-8)

A mixture of 2-7 (430 mg, 1.18 mmol), 2-amino-3-formylpyridine (144 mg,1.18 mmol; for prep., see JOC 1983,48, 3401) and proline (136 mg, 1.18mmol) in absolute ethanol (20 mL) was heated at reflux for 12 h.Following evaporative removal of the solvent, the residue waschromatographed (silica gel, 50% ethyl acetate/chloroform -70:25:5chloroform/ethyl acetate/MeOH) to give 2-8 as a yellow solid.

TLC Rf=0.30 (70:25:5 chloroform/ethyl acetate/MeOH).

¹ H NMR (300 MHz, CDCl₃) δ 9.08 (m, 1 H), 8.16 (dd, J=2.0 Hz, 8.0 Hz 1H), 8.11 (d, J=8.3 Hz, 1 H), 7.42 (m, 2 H), 7.27 (m, 1 H), 7.06 (m, 1H), 6.97 (m, 2 H), 5.66 (m, 1 H),4.11 (m, 2 H), 3.29 (m, 1 H), 2.95-3.07 (m, 5 H), 2.46 (m, 1 H), 2.18 (m, 1 H), 1.98 (m, 2 H), 1.71 (m, 2H), 1.46 (m, 1 H), 1.19 (m, 3 H).

3(S)-(3-Fluorophenyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-prrolidin-1-yl)-propionicacid ethyl ester (2-9)

A mixture of 2-8 (340 mg, 0.7991 mmol) and 10% Pd/carbon (170 mg) inEtOH (10 mL) was stirred under a balloon of hydrogen for 4 h. Followingfiltration and evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH) togive 2-9 as a yellow oil.

TLC Rf=0.16 (70:25:5 chloroform/ethyl acetate/MeOH).

¹ H NMR (300 MHz, CDCl³) δ 7.29 (m, 1 H,), 6.98 (m, 4 H), 6.33 (m, 1 H),5.66 (m, 1 H), 4.76 (b s, 1 H), 4.10 (m, 2 H), 3.38 (m, 1 H),3.28 (m, 1H), 2.95 (m, 3 H), 2.68 (t, J=6.3 Hz, 2 H), 2.55 (m, 2 H), 2.40 (m, 1H), 2.13 (m, 1 H) 1.92 (m, 4 H), 1.61 (m, 3 H), 1.37 (m, 1 H), 1.23 (m,3 H).

3(S)-(3-Fluorophenyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-proyl]-pyrrolidin-1-yl)-propionicacid (2-10 and 2-11)

To a solution of 2-9 (300 mg, 0.6614 mmol) in EtOH (3 mL) was added 1NNaOH (0.725 ml, 0.725 mmol). After stirring for 1 h, the solvents wereevaporated and the residue was chromatographed (silica gel,25:10:1:1-15:10:1:1 ethyl acetate/EtOH/water/NH₄ OH to give 2-10 and2-11 as pure diastereomeric white solids.

TLC Rf=0.31 (2-10) (15:10:1:1 ethyl acetate/EtOH/water/NH₄ OH).

TLC Rf=0.24 (2-11) (15:10:1:1 ethyl acetate/EtOH/water/NH₄ OH).

¹ H NMR (300 MHz, CD₃ OD, 2-10) δ 7.44 (d, J=7.3 Hz, 1 H), 7.37 (m, 1H), 7.14 (m, 1 H), 7.06 (m, 2 H,), 6.50 (d, J=7.3 Hz, 1 H,), 5.78 (m, 1H), 3.55 (m, 1 H), 3.46 (m, 2 H), 3.11 (m, 1 H), 2.61 -2.97 (m, 7H),2.12 (m, 1 H) 1.74-1.95 (m, 7 H).

¹ H NMR (300 MHz, CD₃ OD, 2-11) δ 7.34 (m, 2 H), 7.15 (m, 2 H), 7.03 (m,1 H), 6.47 (d, J=7.3 Hz, 1 H,), 5.50 (m, 1 H), 3.46 (m, 3 H), 3.00 (m, 1H),2.79 (m, 3 H), 2.62 (m, 2 H),2.54 (m, 1 H), 2.23 (m, 1 H), 1.93 (m, 2H), 1.69 (m, 5 H), 1.44 (m, 1 H). ##STR14##

1-Bromo-3-(2,2-diethoxy-ethoxy)-benzene (3-2)

To a suspension of NaH (2.77 g, 115.6 mmol) in DMF (100 mL) at 0° C. wasadded a solution of 3-bromophenol 3-1 in DMF (40 mL) over 40 min. Afterthe addition was complete, the solution was stirred for an additional 30min. The solution was then treated with neat bromoacetaldehyde diethylacetal (17.36 g, 115.6 mmol). The solution was heated at 100° C. for 8h, cooled to room temperature, and extracted with Et₂ O (3×200 mL). Thecombined organic extracts were washed with 10% aq. NaOH (100 mL) andbrine (100 mL), dried over MgSO₄, filtered and concentrated to give 3-2as a yellow oil.

TLC Rf=0.4 (10% ethyl acetate/hexanes).

¹ H NMR (300 MHz, CHCl₃) δ 7.19-7.05 (m, 3 H), 6.85 (d, 1 H), 4.81 (t, 1H, J=6.8 Hz), 3.99 (d, 2 H, J=6.8 Hz), 3.71 (m, 4 H), 1.22 (t, 6 H,J=7.1 Hz)

6-Bromo-benzofuran (3-3)

To a solution of the acetal 3-2 in toluene (200 mL) was addedpolyphosphoric acid (20 g). The biphasic mixture was heated to 100° C.and stirred at this temperature for 4 h. The mixture was cooled to roomtemperature, poured onto ice, and extracted with Et₂ O (2×200 mL). Thecombined organic extracts were washed with saturated aq. NaHCO₃ andbrine. The solution was dried over MgSO₄, filtered, and concentrated.The residue was purified by flash chromatography (100% hexanes) to givethe product 3-3 as a yellow oil.

TLC Rf=0.3 (100% hexanes).

¹ H NMR (300 MHz, CHCl₃) δ 7.68 (s, 1 H), 7.60 (d, 1 H, J=2.1 Hz), 7.46(d, 1 H, J=8.4 Hz), 7.36 (dd, 1 H, J=8.1, 1.5 Hz), 6.75 (dd, 1 H, J=7.1,0.9 Hz).

3-(Benzofuran-6-yl)-acrylic acid ethyl ester (3-4)

A mixture of the 6-bromobenzofuran 3-3 (1.74 g, 8.79 mmol), ethylacrylate (1.09 g, 10.98 mmol), Pd(OAc)₂ (0.099 g, 0.44 mmol),tri-o-tolylphosphine (0.268 g, 0.880 mmol), and sodium acetate (3.60 g,43.9 mmol) in DMF (10 mL) was heated to 100° C. in a sealed tube for 4h. The mixture was cooled to room temperature, diluted with water, andextracted with Et₂ O (2×40 mL). The combined organic extracts werewashed with brine (30 mL), dried over MgSO₄, filtered, and concentrated.The residue was purified by flash chromatography (10% ethylacetate/hexanes) to give the ester 3-4 as an off-white solid.

TLC Rf=0.3 (10% ethyl acetate/hexanes).

¹ H NMR (300 MHz, CHCl₃) δ 7.78 (d, 1 H, J=15.9 Hz), 7.68 (d, 1 H, J=2.4Hz), 7.66 (s, 1 H), 7.59 (d, 1 H, J=8.4 Hz), 7.43 (dd, 1 H, J=9.0, 1.5Hz), 6.78 (m, 1 H), 6.47 (d, 1 H, J=15.9 Hz), 4.27 (q, 2 H, J=7.2 Hz),1.34 (t, 3 H, J=7.2 Hz).

3(S)-(Benzofuran-6-yl)-3-[benzyl-(1(R)-phenyl-ethyl)-amino]-propionicacid ethyl ester (3-5)

A solution of N-benzyl-α-(R)-methylbenzylamine (1.32 g, 6.30 mmol) inTHF (25 mL) at 0° C. was treated with n-BuLi (2.52 mL of a 2.5M soln inhexanes). The resulting solution was stirred at 0° C. for 30 min andthen cooled to -78° C. A solution of acrylate 3-4 (0.681 g, 3.15 mmol)in THF (5 mL) was added. After stirring for 15 min at -78° C., satd. aq.NH₄ Cl soln (5 mL) was added and the cold bath removed. The mixture waswarmed to room temperature, and extracted with Et₂ O (2×40 mL). Thecombined organic extracts were washed with brine (30 mL), dried overMgSO₄, filtered, and concentrated. The residue was purified by flashchromatography (10% ethyl acetate/hexanes) to give the β-aminoester 3-5as a yellow oil.

TLC Rf=0.8 (10% ethanol/dichloromethane).

¹ H NMR (300 MHz, CHCl₃) δ 7.58 (m, 3 H), 7.41 (m, 2 H), 7.22 (m, 9 H),7.59 (s, 1 H), 4.58 (m, 1 H), 4.05 (m, 1 H), 3.91 (q, 2 H, J=7.1 Hz),3.72 (m, 2 H), 2.62 (m, 2 H), 1.21 (d, 3 H, J=7.2 Hz), 1.03 (t, 3 H,J=7.1 Hz).

3(S)-Amino-3-(2,3-dihydro-benzofuran-6-yl)-propionic acid ethyl ester(3-6)

A mixture of the dibenzylamine 3-5 (1.19 g, 2.78 mmol) in EtOH/H₂ O/AcOH(26 mL/3 mL/1.0 mL) was degassed with argon and treated with Pd(OH)₂(1.19 g). The mixture was placed under 1 atm of H₂. After stirring for18 h, the mixture was diluted with EtOAc, and filtered through celite.The filtrate was concentrated and the residue purified by flashchromatography (10% ethyl acetate/dichloromethane) to give the ester 3-6as a white solid.

TLC Rf=0.25 (10% ethanol/dichloromethane).

¹ H NMR (300 MHz, CD₃ OD) as the trifluoroacetate salt: δ 7.25 (d, 1 H,J=8.1 Hz), 6.88 (m, 1 H), 7.66 (s, 1 H), 6.82 (s, 1 H), 4.58 (m, 3 H),4.12 (m, 2 H), 3.30 (m, 1 H), 3.19 (m, 2 H), 2.98 (m, 2 H), 1.11 (t, 3H, J=7.2 Hz). ##STR15##

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(3-[3-(2-methyl-[1,3]dioxolan-2-yl)-propyl]-2-oxo-pyrrolidin-1-yl)-propionicacid ethyl ester (4-1)

A mixture of 2-5 (440 mg, 1.6 mmol), 3-6 (400 mg, 1.5 mmol), Na(OAc)₃ BH(469 mg, 2.25 mmol) and NEt₃ (0.41 mL, 3.0 mmol) in dichloroethane (10mL) was stirred for 48 h. The mixture was diluted with ethyl acetate,washed with sat. NaHCO₃, brine, and dried over MgSO₄. Followingevaporative removal of the solvent, the residue was chromatographed(silica gel, 50:35:14:1 hexanes/chloroform/ethyl acetate/MeOH) to give4-1 as a white solid.

TLC R_(f) =0.45 (silica, 70:25:5 chloroform/ethyl acetate/MeOH)

¹ H NMR (300 MHz, CDCl₃) δ 7.15 (m, 1 H), 6.78 (m, 1 H), 6.70 (m 1 H),5.63 (m, 1 H), 4.58 (m, 2 H), 4.12 (q, J=7 Hz, 2 H), 3.92 (m, 4 H),3.40-2.80 (m, 6 H), 2.38 (m, 1 H), 2.14 (m, 1 H), 1.86 (m, 1 H), 1.64(m, 4 H), 1.42 (m, 2 H), 1.30 (m, 3 H), 1.22 (t, J=7 Hz, 3 H).

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[2-oxo-3-(4-oxo-pentyl)-pyrrolidin-1-yl]-propionicacid ethyl ester (4-2)

A solution of 4-1 (600 mg, 1.4 mmol), p-TSA (20 mg) and acetone (50 mL)was heated at reflux for 4 hr. The cooled reaction mixture was dilutedwith EtOAc and then washed with sat. NaHCO₃ and brine, dried (MgSO₄),and concentrated to afford 4-2 as a colorless oil.

¹ H NMR (300 MHz, CDCl₃) δ 7.15 (m, 1 H), 6.78 (m, 1 H), 6.70 (m 1 H),5.63 (m, 1 H), 4.58 (m, 2 H), 4.12 (q, J=7 Hz, 2 H), 3.35-2.90 (m, 6 H),2.49-2.30 (m, 3 H), 2.13 (2 s, 3 H), 1.90-1.50 (m, 5 H), 1.33 (m, 1 H),1.22 (t, J=7 Hz, 3 H).

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[3-(3-[1,8]naphthyridin-2-yl-propyl)-2-oxo-pyrrolidin-1-yl]-propionicacid ethyl ester (4-3)

A mixture of 4-2 (540 mg, 1.4 mmol), 2-amino-3-formylpyridine (170 mg,1.4 mmol; for prep. see JOC 1983, 48, 3401) and proline (161 mg, 1.4mmol) in absolute ethanol (20 mL) was heated at reflux for 12 h.Following evaporative removal of the solvent, the residue waschromatographed (silica gel, 50% ethyl acetate/chloroform 70:25:5chloroform/ethyl acetate/MeOH) to give 4-3 as a yellow oil.

TLC Rf=0.21 (70:25:5 chloroform/ethyl acetate/MeOH).

¹ H NMR (300 MHz, CDCl₃) δ 9.08 (m, 1 H), 8.16 (dd, J=2.0 Hz, 8.0 Hz 1H), 8.11 (d, J=8.3 Hz, 1 H), 7.42 (m, 2 H), 7.10 (m, 1 H), 6.78 (m, 1H), 6.70 (m, 1 H), 5.63 (m, 1 H),4.57 (m, 2 H), 4.11 (m 2 H), 3.29 (m, 1H), 3.30-2.80 (m, 9 H), 2.40 (m, 1 H), 2.18 (m, 1 H), 1.98 (m, 2 H),1.70-1.50 (m, 2 H), 1.46 (m, 1 H), 1.19 (m, 3 H).

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid ethyl ester (4-4)

A mixture of 4-3 (460 mg, 1.0 mmol) and 10% Pd/carbon (300 mg) in EtOH(20 mL) was stirred under a balloon of hydrogen for 3 h. Followingfiltration and evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH) togive 4-4 as a yellow oil.

TLC Rf=0.15 (70:25:5 chloroform/ethyl acetate/MeOH).

¹ H NMR (300 MHz, CDCl₃) δ 7.18 (m, 1 H,), 7.07 (m, 2 H), 6.80 (m, 1 H),6.70 (m, 1 H), 6.37 (m, 1 H), 5.64 (m, 1 H), 4.76 (bs, 1 H), 4.55 (m, 2H), 4.10 (q, J=7 Hz, 2 H), 3.40 (m, 1 H), 3.28 (m, 2 H), 3.28 (m, 1 H),3.19 (m, 2 H), 3.00 (m, 1 H), 2.95 (m, 2 H), 2.69 (m 2 H), 2.55 (m, 2H), 2.37 (m, 1 H), 2.13 (m, 1 H) 1.92 (m, 3 H), 1.75-1.30 (m, 4 H), 1.23(m, 3 H).

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid (4-5 and 4-6)

To a solution of 4-4 (380 mg, 0.79 mmol) in EtOH (2 mL) was added 1NNaOH (0.93 ml, 0.93 mmol). After stirring for 1 h, the solvents wereevaporated and the residue was chromatographed (silica gel,25:10:1:1-15:10:1:1 ethyl acetate/EtOH/water/NH₄ OH) to give 4-5 and 4-6as pure diastereomeric white solids.

TLC Rf=0.37 (isomer A) (15:10:1:1 ethyl acetate/EtOH/water/NH₄ OH).

TLC Rf=0.28 (isomer B) (15:10:1:1 ethyl acetate/EtOH/water/NH₄ OH).

¹ H NMR (300 MHz, CD₃ OD, Isomer A) δ 7.44 (d, J=7 Hz, 1 H), 7.16 (d,J=7 Hz, 1 H), 6.80 (d, J=7 Hz, 1 H,), 6.70 (s, 1 H), 6.48 (d, J=7 Hz, 1H,), 5.46 (m, 1 H), 4.50 (m, 2 H), 3.60-2.50 (m, 13 H), 1 H), 2.15-1.70(m, 8 H), ¹ H NMR (300 MHz, CD₃ OD, Isomer B) δ 7.40 (d, J=7 Hz, 1 H),7.13 (d, J=7 Hz, 1 H), 6.80 (d, J=7 Hz, 1 H,), 6.68 (s, 1 H), 6.50 (d,J=7 Hz, 1 H,), 5.72 (m, 1 H), 4.53 (m, 2 H), 3.44 (m, 3 H), 3.15 (m, 4H), 2.97 (m, 1 H), 2.70-2.40(m, 6 H), 2.20 (m, 1 H), 2.00-1.40 (m, 6 H).##STR16##

3-Quinolin-3-yl-propionic acid (5-2)

A solution containing quinoline-3-carboxaldehyde 5-1 (5 g, 31.8 mmol),malonic acid (3.6 g, 35.0 mmol), and ammonium acetate (5.0 g, 63.6 mmol)in anhydrous ethanol (125 mL) was heated at reflux for 12 h. Aftercooling to room temperature, the resulting white solid was collected byfiltration and washed with cold ethanol (150 mL) and then dried undervacuum to provide 5-2 as a white solid (3.84 g, 17.8 mmol, 56%).

¹ H NMR (300 MHz, D₂ O): δ 8.91 (d, J=2 Hz 1 H), 8.21 (d, J=2 Hz, 1 H),8.12 (d, J=8 Hz, 1 H), 7.84 (d, J=7 Hz, 1 H), 7.72 (t, J=7 Hz, 1 H),7.54 (t, J=7 Hz, 1 H), 4.72 (m, 1 H), 2.73 (m, 2 H).

3-Phenylacetylamino-3-(quinolin-3-yl)-propionic (5-3)

A 0° solution of 5-2 (3.5 g, 16.2 mmol) and NaHCO₃ (2.7 g, 32.4 mmol) in50% aqueous dioxane (100 mL) was treated dropwise with a solution ofphenylacetyl chloride (3.00 g, 19.4 mmol) in 25 mL of dioxane. Theresulting solution was stirred at 0° for 2.5 h., then warmed to roomtemperature, diluted with H₂ O (50 mL) and washed with ether (2×100 mL).The aqueous layer was adjusted to pH=3 with 3N HCl and then extractedwith CH₂ Cl₂ (3×150 mL). The pooled organic extracts were dried,filtered and concentrated to afford 5-3 as an off-white solid.

¹ H NMR (300 MHz, CD₃ OD): δ 8.85 (d, J=2 Hz 1 H), 8.20 (d, J=2 Hz, 1H), 8.00 (d, J=8 Hz, 1 H), 7.86 (d, J=7 Hz, 1 H), 7.76 (t, J=7 Hz, 1 H),7.52 (t, J=7 Hz, 1 H), 7.28 (m, 6 H), 5.53 (t, J=6.8 Hz, 1 H), 3.57 (s,2 H), 2.96 (m, 2 H).

3(S)-(Quinolin-3-yl)-propionic acid dihydrochloride (5-6)

Acid 5-3 (5.0 g, 15 mmol) was suspended in water (3.5 L), then treatedwith 1N NaOH (15 mL) to afford a clear solution. Penicillin amidase(Sigma, EC 3.5.1.11, 10,000 U) in 0.1M phosphate buffer was added. ThepH of the mixture was adjusted to 7.8 with 1N NaOH and the solution wasstirred at room temperature for 4 days. The reaction was monitoredperiodically by HPLC and the reaction stopped once the 50% conversionwas reached. Next, the reaction solution was cooled to 0° C. andadjusted to pH=3 with 3N HCl. An oily yellow precipitate formed whichwas collected by filtration, then washed with water to afford crude 5-5(1.8 g, 5.3 mmol). The filtrate was extracted with CH₂ Cl₂ (3×500 mL) toafford additional 5-5 contaminated by phenylacetic acid. Both batches ofcrude 6 were combined and stirred in 6N HCl (200 mL) at 50° for 12 hthen cooled, washed with ether (2×100 mL) and evaporated to afford 5-6.

3(S)-(Quinolin-3-yl)-propionic acid ethyl ester dihydrochloride (5-7).

The resolved acid 5-6 was converted to 5-7 by refluxing in ethanolicHCl.

¹ H NMR (300 MHz, CD₃ OD): δ 9.25 (d, J=2 Hz 1 H), 8.31 (d, J=2 Hz, 1H), 8.15 (d, J=8 Hz, 1 H), 7.84 (d, J=7 Hz, 1 H), 7.72 (t, J=7 Hz, 1 H),7.54 (t, J=7 Hz, 1 H), 4.72 (m, 1 H), 4.15 (q, J=6 Hz, 2 H), 2.73 (m, 2H) 1.18 (t, J=6 Hz, 3 H). ##STR17##

3(S)-(Quinolin-3-yl)-3-(3-[3-(2-methyl-[1,3]dioxolan-2-yl)-propyl]-2-oxo-pyrrolidin-1-yl)-propionicacid ethyl ester (6-1)

A mixture of 2-5 (377 mg, 1.3 mmol), 5-6 (400 mg, 1.3 mmol), Na(OAc)₃ BH(400 mg, 2.0 mmol) and NEt₃ (0.35 mL, 2.6 mmol) in dichloroethane (10mL) was stirred for 24 h. The mixture was diluted with ethyl acetate,washed with sat. NaHCO₃, brine, and dried over MgSO₄. Followingevaporative removal of the solvent, the residue was chromatographed(silica gel, 50:35:14:1 hexanes/chloroform/ethyl acetate/MeOH) to give6-1 as a yellow oil.

TLC R_(f) =0.47 (silica, 70:25:5 chloroform/ethyl acetate/MeOH)

¹ H NMR (300 MHz, CDCl₃) δ 8.85 (m, 1 H), 8.10-7.40 (m, 5 H), 5.90 (m, 1H), 4.12 (q, J=7 Hz, 2 H), 3.90 (m, 4 H), 3.38 (m, 1 H), 3.20-2.95 (m, 3H), 2.40 (m, 1 H), 2.14 (m, 1 H), 1.90 (m, 1 H), 1.74-1.30 (m, 4 H),1.30 (ds, 3 H), 1.22 (t, J=7 Hz, 3 H).

3(S)-(Quinolin-3-yl)-3-[2-oxo-3-(4-oxo-pentyl)-pyrrolidin-1-yl]-pronionicacid ethyl ester (6-2)

A solution of 6-1 (380 mg, 1.0 mmol), p-TSA (20 mg) and acetone (50 mL)was heated at reflux for 4 hr. The cooled reaction mixture was dilutedwith EtOAc and then washed with sat. NaHCO₃ and brine, dried (MgSO₄),and concentrated to afford 6-2 as a yellow oil.

¹ H NMR (300 MHz, CDCl₃) δ 8.74 (m, 1 H), 8.05-7.40 (m, 5 H), 5.90 (m, 1H), 4.13 (m, 2 H), 3.38 (m, 1 H), 3.20-2.95 (m, 3 H), 2.50-2.10 (m, 4H), 2.13 (d, J=5 Hz, 3 H), 1.90-1.20 (m, 6 H), 1.22 (t, J=7 Hz, 3 H).

3(S)-(Quinolin-3-yl)-3-[3-(3-[1,8]naphthyridin-2-yl-propyl)-2-oxo-pyrrolidin-1-yl]-propionicacid ethyl ester (6-3)

A mixture of 6-2 (396 mg, 1.0 mmol), 2-amino-3-formylpyridine (138 mg,1.2 mmol; for prep. see JOC 1983, 48, 3401) and proline (218 mg, 2.0mmol) in absolute ethanol (15 mL) was heated at reflux for 12 h.Following evaporative removal of the solvent, the residue waschromatographed (silica gel, 50% ethyl acetate/chloroform to 70:25:5chloroform/ethyl acetate/MeOH) to give 6-3 as a yellow oil.

TLC Rf=0.23 (70:25:5 chloroform/ethyl acetate/MeOH).

¹ H NMR (300 MHz, CDCl₃) δ 9.08 (m, 1 H), 8.85 (m, 1 H), 8.20-7.50 (m, 9H), 5.90 (m, 1 H), 4.11 (m, 2 H), 3.40 (m, 1 H), 3.20-2.90 (m, 6 H),2.60-1.40 (m, 6 H), 1.22 (m, 3 H).

3(S)-(Quinolin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-proyl]-pyrrolidin-1-yl)-propionicacid ethyl ester (6-4)

A mixture of 6-3 (380 mg, 0.8 mmol) and 10% Pd/carbon (200 mg) in EtOH(20 mL) was stirred under a balloon of hydrogen for 6 h. Followingfiltration and evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:25:5 to 70:20:10 chloroform/ethylacetate/MeOH) to give 6 as a yellow oil.

TLC Rf=0.20 (70:20:10 chloroform/ethyl acetate/MeOH).

¹ H NMR (300 MHz, CDCl₃) δ 8.86 (m, 1 H), 8.08 (m, 2 H), 7.80 (m, 1 H),7.72 (m, 1 H), 7.57 (m, 1 H), 7.03 (m, 1 H), 6.33 (m, 1 H), 5.90 (m, 1H), 4.11 (m, 2 H), 3.40 (m, 3 H), 3.15-2.00 (m, 9 H), 2.00-1.30 (m, 8H), 1.22 (m, 3 H).

3(S)-(Quinolin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid (6-5 and 6-6)

To a solution of 6-4 (300 mg, 0.62 mmol) in EtOH (3 mL) was added 1NNaOH (0.68 ml, 0.68 mmol). After stirring for 2 h, the solvents wereevaporated and the residue was chromatographed (silica gel,25:10:1:1-15:10:1:1 ethyl acetate/EtOH/water/NH₄ OH) to give 6-5 and 6-6as pure diastereomeric white solids.

TLC Rf=0.32 (isomer A) (10:10:1:1 ethyl acetate/EtOH/water/NH₄ OH).

TLC Rf=0.28 (isomer B) (10:10:1:1 ethyl acetate/EtOH/water/NH₄ OH).

¹ H NMR (300 MHz, CD₃ OD, Isomer A) δ 8.85 (d, J=2 Hz, 1 H), 8.33 (bs, 1H), 8.00 (m, 2 H), 7.78 (m, 1 H), 7.44 (d, J=7 Hz, 1 H), 6.50 (d, J=7Hz, 1 H,), 6.02 (m, 1 H), 3.62 (m, 1 H), 3.48 (m, 2 H), 3.20-1.90 (m, 3H), 2.80-2.60 (m, 4 H), 2.13 (m, 1 H), 2.00-1.70 (m, 8 H).

¹ H NMR (300 MHz, CD₃ OD, Isomer B) δ 8.85 (d, J=2 Hz,, 1 H), 8.33 (bs,1 H), 8.00 (m, 1 H), 7.95 (m, 1 H), 7.75 (m, 1 H), 7.62 (m, 1 H), 7.33(d, J=7 Hz, 1 H), 6.43 (d, J=7 Hz, 1 H,), 5.74 (m, 1 H), 3.55 (m, 1 H),3.40 (m, 2 H), 3.20-1.95 (m, 2 H), 2.72 (m, 2 H), 2.58 (m, 3 H), 2.23(m, 1 H), 2.00-1.40 (m, 8 H). ##STR18##

1-(4-(S)-benzyl-2-oxo-oxazolidin-3-yl)-heptane-1,6-dione (7-2)

To a stirred solution of 6-oxo-heptanoic acid 7-1(100 g, 694 mmol), NEt₃(111.3 ml, 763.4 mmol) and THF (2000 mL) at -78° C. was added pivaloylchloride (98.7 ml, 763.4 mmol). The mixture was warmed to 0° C. for 1.0h and then recooled to -78° C. To a stirred solution of(S)-(-)-4-benzyl-2-oxazolidinone (136 g, 763.4 mmol) and THF (2000 ml)at -78° C. was added nBuLi (306 ml, 765 mmol, 2.5M in hexanes) dropwiseover 30 minutes. After 20 minutes, the lithium reagent was transferredto the mixed anhydride via cannula. After 20 minutes, the reaction waswarmed to 0° C. for 1.0 h. The mixture was diluted with ethyl acetate,washed with sat. NaHCO₃, brine, and dried over MgSO₄. Followingevaporative removal of the solvent, the residue was azeotroped withxylenes to give 7-2 as a colorless foam.

TLC R_(f) =0.25 (silica, 25% EtOAc/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 7.27, (m, 5H), 4.66 (m, 1H), 4.16 (m, 2H),3.29 (dd, J=3 Hz, 13 Hz, 1H),2.90 (m, 2H), 2.75 (m, 1H), 2.50 (t, J=7Hz, 2H), 2.15 (s, 3H), 1.68 (m, 4H).

4-(S)-benzyl-3-[5-(2-methyl-[3]dioxolan-2-yl)-oentanoyl]-oxazolidin-2-one(7-3)

A mixture of ketone 7-2 (695 nmol), ethylene glycol (59 ml, 1040 nmmol),p-TSA (500 mg, 2.713 mmol) and benzene (2000 mL) was heated to refluxwith azeotropic removal of water for 12 hours. The reaction mixture wasdiluted with EtOAc and then washed with sat. NaHCO₃, brine, dried(MgSO₄), and concentrated to give 7-3 as a yellow oil.

TLC R_(f) =0.25 (silica, 30% EtOAc/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 7.26 (m, 5H), 4.67 (m, 2H), 3.94 (s, 4H),3.29 (m, 1H), 2.95 (m, 2H), 2.76 (m, 1H), 1.71 (m, 4H), 1.50 (m, 2H),1.32 (s, 3H).

4-(S)-benzyl-3-(R)-{2-[3-(2-methyl-[3]dioxolan-2-yl)-propyl]-pent-4-enoyl}-oxazolidin-2-one(7-4)

To a stirred solution of 7-3 (695 mmol) and THF (2000 mL) at -78° C. wasadded LiN(TMS)₂ (915 mL, 915 mmol, 1.0 M in THF) dropwise over 30minutes. After 20 minutes, allyl bromide was added. After 20 minutes,the reaction was warmed to 0° C. After 4.0 h, the reaction was dilutedwith EtOAc, washed with sat. NaHCO₃, brine, dried (MgSO₄) andconcentrated. Flash chromatography (silica, 25% EtOAc/hexanes) gave 7-4as a yellow oil.

TLC R_(f) =0.27 (silica, 30% EtOAc/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 7.25 (m 5H), 5.81 (m, 1H), 5.05 (m, 2H), 4.67(m, 1H), 4.18 (m, 2H), 3.91 (m, 4H), 3.29 (dd, J=3Hz, 13Hz, 1H), 2.67(m, 1H), 2.48 (m, 1H), 2.32 (m, 2H), 1.76 (m, 1H) 1.63 (m, 2H), 1.55 (m,1H), 1.40 (m, 2H), 1.28 (s, 3H).

3-(R)-(4-(S)-benzyl-2-oxo-oxazolidine-3-carbonyl)-6-(2-methyl-[3]dioxolan-2-yl)-hexanal(7-5)

To a stirred solution of 7-4 (60 g, 155 mmol), sudan III (20 mg) and CH₂Cl₂ (1500 mL) at -78° C. under argon was bubbled ozone until redsolution changed to yellow-orange. The solution was purged with argonfor 30 minutes. PPh₃ (61 g, 233 mmol) was added followed by the removalof the cooling bath. After 2.0 h, the reaction was concentrated. Flashchromatography (silica, 20%-40% EtOAc/hexanes) gave 7-5 as a yellow oil.

TLC R_(f) =0.15 (silica, 50% EtOAc/hexanes)

¹ H NMR (300 MHZ, CDCl₃) δ 7.27 (M 5H), 4.65 (M, 1H), 4.22 (M, 3H), 3.91(M, 4H), 3.28 (DD, J=3HZ, 13HZ, 1H), 3.05 (M, 1H), 2.78 (M, 2H), 1.69(M, 3H), 1.50 (M, 3H), 1.29 (S, 3H).

3(S)-(3-Fluorophenyl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid (2-10)

The title compound was prepared following the synthetic proceduredepicted in Scheme 2, but replacing intermediate 2-5 with the chiralintermediate 7-5, the preparation of which is shown in Scheme 7.

3(S)-(3-Fluorophenyl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid (2-11)

The title compound was prepared in a similar fashion as itsdiastereoisomer 7-6 immediately above, but using the enantiomer of 7-5prepared in an analogous fashion to that depicted in Scheme 7. ##STR19##

4-[8]Naphthyridin-2-yl-butyronitrile (8-2)

A mixture of 5-oxo-hexanenitrile (8-1) (5 ml, 43.8 mmol),2-amino-3-formylpyridine (7 g, 57 mmol), proline (5.3 g, 43.8 mmol) andethanol (100 mL) was heated at reflux for 12 hours. Followingevaporation of the solvent, the residue was chromatographed (silica gel,ethyl acetate) to give 8-2 as a white solid.

TLC R_(f) =0.21 (silica, ethyl acetate).

¹ H NMR (300 MHz, CDCl₃) δ 9.10 (m, 1H), 8.19 (m, 2H), 7.47 (m, 2H),3.24 (t, 2H, J=7 Hz), 2.55 (t, 2H, J=7Hz), 2.39 (m, 2H).

4-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-butyronitrile (8-3)

A mixture of 8-2 (14 g, 71 mmol), 10% Pd/C (2 g) and ethanol (200 mL)was stirred under a balloon of hydrogen gas for 1 h. Filtration andevaporation produced 8-3 as a white solid.

¹ H NMR (300 MHz, CDCl₃) δ 7.06 (d, 1H, J=7 Hz), 6.35 (d, 1H, J=7 Hz),4.76 (br s, 1H), 3.41 (m, 2H), 2.71 (m, 4H), 2.38 (t, 2H, J=7 Hz), 2.08(m, 3H), 1.85 (m, 2H), 1.80 (m, 1H).

2(S)-tert-Butoxycarbonylamino-3-[3-(3-[1,8]naphthyridin-2-yl-propyl)-[1,2,4]oxadiazol-5-yl]-propionicacid benzyl ester (8-5)

To methanol (20 mL) was added sodium metal (0.86 g, 37 mmol). After 30minutes, this solution was added to a suspension of hydroxylaminehydrochloride (2.57 g, 37 mmol) in methanol (5 mL). After stirring for30 min, the mixture was filtered. To this filtrate was added 8-3 (5 g,24.4 mmol), and the mixture stirred for 24 h at 40° C. An additionalportion of hydroxylamine (50 mmol, prepared as above) was then addedfollowed by a further 24 h of stirring. The resulting mixture wasdiluted with ethyl acetate, washed with sat. NaHCO₃, brine, and driedover MgSO₄. Evaporation gave crude amide oxime (8-4). To a solutionN-BOC-(L)-aspartic acid-alpha benzyl ester (1.5 g, 4.6 mmol) in THF (20mL) at 0° C. was added N-methylmorpholine (0.61 mL, 5.5 mmol) followedby isobutyl chloroformate (0.66 mL, 5.1 mmol). After 30 minutes, asolution of the above crude oxime in DMF (5 mL) was added. The solutionwas allowed to warm to 25° C. and stir for 1 h, then toluene (20 mL) wasadded and the mixture heated to 110° C., allowing the THF to evaporate.The resulting mixture was heated at reflux for 6 h. Following cooling,the mixture was diluted with ethyl acetate, washed with sat. NaHCO₃,brine, and dried over MgSO₄. The residue was chromatographed (silicagel, 50-60% ethyl acetate/hexanes) to give 8-5 as a yellow oil.

TLC R_(f) =0.63 (silica, ethyl acetate).

¹ H NMR (300 MHz, CDCl₃) δ 7.30 (m, 5H), 7.04 (m, 1H), 6.34 (m, 1H),5.16 (s, 2H), 4.80 (m, 2H), 3.41 (m, 2H), 2.68 (m, 4H), 2.59 (m, 2H),2.04 (m, 2H), 1.85 (m, 4H), 1.43 (m, 9H).

2(S)-Benzenesulfonylamino-3-[3-(3-[1,8]naphthyridin-2-yl-propyl)-[1,2,4]oxadiazol-5-yl]-propionicacid (8-7)

A solution of 4M HCl in dioxane (20 mL) was added to 8-5 (0.7 g, 1.4mmol). After 30 minutes, the solvent was evaporated to give a whitesolid. To this solid (0.3 g, 0.64 mol) was added dichloromethane (10mL), and NMM (0.7 mL, 6.4 mmol), and the mixture was cooled to 0° C.Phenylsulfonyl chloride (0.081 mL, 0.64 mmol) was added. After 30minutes, the mixture was diluted with ethyl acetate, washed with sat.NaHCO₃, brine, and dried over MgSO₄. Evaporation gave the crude ester8-6, which was dissolved in ethanol (5 mL); sodium hydroxide (0.7 mL, 1N in water) was added. After 1 hr, the solvent was evaporated, and theresidue was chromatographed (silica gel, 25:10:1:1 followed by 15:10:1:1ethyl acetate /EtOH /water NH₄ OH) to give 8-7 as a white solid.

TLC Rf=0.48 (10:10:1:1 ethyl acetate/EtOH/water/NH₄ OH).

¹ H NMR (300 MHZ, CD₃ OD) A 7.68 (M, 2H), 7.33 (M, 3H), 7.15 (D, 1H, J=7HZ), 6.39 (D, 1H, J=7 HZ), 3.91 (M, 1H), 3.37 (M, 2H), 3.08 (M, 2H),2.71 (M, 2H), 2.57 (M, 4H), 1.97 (M, 2H), 1.88 (M, 2H). ##STR20##

5-Bromo-2-ethoxypyridine (9-2)

Sodium metal (4.87 g, 0.212 mol) was added to ethanol (200 mL) andstirred until completely dissolved. To this solution was added2,5-dibromopyridine 9-1 (10 g, 0.0424 mol) and the resulting mixture wasstirred at reflux for 16 hr. The solvent was removed in vacuo and theresidue partitioned between water and EtOAc. After extraction with EtOAc(2×), the organic layer was washed with brine, dried (MgSO₄) andconcentrated to give 9-2 as a red-brown solid which was used as such inthe next step.

¹ H NMR (300 MHz, CDCl₃) δ 1.4 (3H, t), 4.33 (2H, q), 6.63 (1H, d), 7.62(1H, dd), 8.19 (1H, d).

3(S)-(6-Ethoxypyridin-3-yl)-β-alanine ethyl ester (9-3)

The title compound 9-3 was prepared from 9-2 using the proceduredescribed for the synthesis of 19-5 from 19-3.

¹ H NMR (300 MHz, CDCl₃): δ 1.25 (3H, t), 1.39 (3H, t), 2.61 (1H, dd),2.67 (11H, dd), 4.15 (2H, q), 4.34 (2H, q), 4.40 (1H, dd), 6.71 (1H, d),7.62 (1H, dd), 8.11 (1H, d). ##STR21##

3-(6-Amino-pyridin-3-yl)-acrylic acid tert-butyl ester (10-2)

A mixture of 2-amino-5-bromopyridine 10-1 (10 g, 58 mmol), tert-butylacrylate (50 mL, 344 mmol), triethylamine (50 mL, 359 mmol),tri-o-tolylphosphine (3.0 g, 9.8 mmol) and Pd(OAc)₂ (1.0 g, 4.5 mmol) in150 mL CH₃ CN was purged with argon for 5 min and subsequently refluxedat 110° C. for 20 hr. The mixture was then cooled and concentrated. Theresidue was purified using silica gel flash chromatography(EtOAc/hexanes 1:1) to afford the desired product 10-2 as a solid.

Rf (silica, EtOAc/hexanes 1:1)=0.26

3(S)-(6-Amino-pyridin-3-yl)-3-[benzyl-(1(R)-phenylethyl)-amino]-propionicacid tert-butyl ester (10-3)

To a cooled (0° C.) solution of (R)-(+)-N-benzyl-α-methylbenzylamine(4.0 g, 19 mmol) in 50 mL THF was gradually added n-butyllithium (11.3mL, 2.5 M, 28.2 mmol) over 5 min. The mixture was stirred for 30 min at0° C. and cooled to -78° C. A solution of 10-2 (2.0 g, 9.4 mmol) in 20mL THF was gradually added. After stirring for 40 min at -78° C., it wastreated with NH₄ Cl (sat.) at -78° C., warmed to room temperature andextracted three times with EtOAc. The combined organic layers werewashed with brine and dried over Na₂ SO₄. After solvent evaporation, theresidue was purified using silica gel flash chromatography(EtOAc/hexanes 1:2) to afford the desired product 10-3 as an oil.

Rf (silica, EtOAc/hexanes 1:1)=0.28

3(S)-Amino-3-(6-amino-pyridin-3-yl)-propionic acid ethyl ester.2 HCl(10-4)

A mixture of 10-3 (0.5 g, 1.2 mmol) and 10% Pd/C (0.4 g) in 10 mL AcOHwas purged with argon for 5 min and then heated at 78° C.1,4-Cyclohexadiene (2 mL. 21.1 mmol) was then gradually added. Thereaction mixture was stirred for 3 hr and filtered through a celite pad.The solution was concentrated and the residue was purified using silicagel flash chromatography (EtOAc/MeOH/NH₄ OH 1:1:0.04) to afford an oil.To the oil (1.2 g) in 20 mL ETOH was introduced HCl gas for 10 min. Themixture was stirred 24 hr and then concentrated to afford the desiredproduct 10-4 as the HCl salt.

¹ H NMR (400 MHz, CD₃ OD) δ 8.11 (d, J=9.6 Hz, 1H), 8.08 (s, 1H), 7.13(d, J=9.6 Hz, 1H), 4.77 (m, 1H), 4.18 (q, J=6.8 Hz, 2H), 3.22-3.02 (m,2H), 1.24 (t, J=6.8 Hz, 3H). ##STR22##

3-(3-Hydroxy-4-nitrophenyl)-acrylic acid ethyl ester (11-2)

To a stirred solution of aldehyde 11-1 (20.28 g, 132.5 mmol) in CH₂ Cl₂(400 mL) at room temperature was added(carbethoxymethylene)triphenylphosphorane (46.12 g, 132.5 mmol) over a10 min period. The resulting orange solution was stirred at roomtemperature for 2 h. The solution was concentrated to one-fourth itsvolume. Flash chromatography (silica gel; 30:70 EtOAc/hexanes) gave thetitle compound 11-2 as a bright yellow solid.

TLC Rf=0.75 (25:75 EtOAc/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 8.14 (d, 1H), 7.60 (d, 1H), 7.15 (dd, 1H),6.54 (d, 1H), 4.30 (q, 2H), 1.36 (t, 3H).

3-(4-Amino-3-hydroxyphenyl)-acrylic acid ethyl ester (11-3)

To a stirred suspension of 11-2 (4.64 g, 19.6 mmol), NH₄ Cl (524 mg, 9.8mmol), EtOH (140 mL) and H₂ O (70 mL) was added iron dust (2.72 g, 48.9mmol). The resulting yellow suspension was refluxed for 1.5 h., and thenthe solution was filtered while hot through celite. The filtrate wasconcentrated and the residue was partitioned between EtOAc and brine.The layers were separated and the EtOAc layer dried (Na₂ SO₄) andconcentrated to give 11-3 which was used without further purification inthe next step.

TLC Rf=0.2 (25:75 EtOAc/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 7.57 (d, 1H), 7.00 (m, 2H), 6.68 (d, 1H),6.20 (d, 1H), 4.26 (q, 2H), 4.10 (b, 2H), 1.33 (t, 3H).

3-[4-(2-Chloroacetylamino)-3-hydroxyphenyl]acrylic acid ethyl ester(11-4)

To a stirred solution of 11-3 (3.38 g, 16.3 mmol) in CHCl₃ (80 mL) wasadded saturated NaHCO₃ (50 mL) and it was then chilled to 0° C. Asolution of chloroacetyl chloride (1.94 mL, 24.4 mmol) in CHCl₃ (30 mL)was added dropwise to the chilled biphase. Upon addition completion, thereaction was stirred at 0° C. for 1 h. The layers were separated and theaqueous layer was extracted twice with EtOAc. The combined organiclayers were washed with brine, dried (Na₂ SO₄) and concentrated to give11-4 which was used without further purification in the next step.

TLC Rf=0.4 (25:75 EtOAc/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 10.33 (s, 1H), 9.58 (s, 1H), 8.02 (d, 1H),7.51 (d, 1H), 7.19 (d, 1H), 7.12 (s, 1H), 6.39 (d, 1H), 4.42 (s, 2H),4.17 (q, 2H), 1.25 (t, 3H).

3-(3-Oxo-3,4-dihydro-2H-benzo[4]oxazin-7-yl) acrylic acid ethyl ester(11-5)

To a stirred solution of 11-4 (4.28 g, 15.0 mmol) in DMF (50 mL) wasadded K₂ CO₃ (4.50 g, 32.6 mmol). The resulting suspension was heated to50° C. for 12 h., after which time the reaction was concentrated. Theresidue was partitioned between saturated NaHCO₃ and EtOAc and extractedtwice with EtOAc. The combined organic layers were washed with brine,dried (Na₂ SO₄), and concentrated. Flash chromatography (silica gel;25:75 EtOAc/hexanes) yielded 11-5 as a beige solid.

TLC Rf=0.5 (25:75 EtOAc/hexanes).

¹ H NMR (300 MHz, CDCl₃) δ 10.91 (s, 1H), 7.54 (d, 1H), 7.37 (s, 1H),7.31 (d, 1H), 6.90 (d, 1H), 6.51 (d, 1H), 4.60 (s, 2H), 4.16 (q, 2H),1.24 (t, 3H).

3-(R)-[Benzyl-(1-phenylethyl)-amino]-3-(S)-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)propionic acid ethyl ester (11-6)

To a stirred solution of (R)-(+)-N-benzyl-α-methylbenzylamine (5.43 g,25.7 mmol) and anhydrous THF (75 mL) at 0° C. was added butyllithium(10.3 mL, 2.5 M/hexanes, 25.7 mmol) via syringe. The violet-red solutionwas stirred at 0° C. for 15 minutes and then cooled to -78° C. Asolution of 11-5 (2.12 g, 8.6 mmol) in anhydrous THF (50 mL) was addedvia syringe, and the resulting brown solution was stirred at -78° C. for30 minutes. The brown solution was quenched with saturated NH₄ Cl, themixture then warmed to room temperature and extracted twice with Et₂ O.The combined organic layers were washed with brine, dried (Na₂ SO₄), andconcentrated. Flash chromatography (silica gel; 15:85 to 25:75EtOAc/hexanes) yielded 11-6 as a white foam.

TLC Rf=0.25 (25:75 EtOAc/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 10.89 (s, 1H), 7.32 (m, 10H), 7.10 (m, 2H),6.91 (d, 1H), 4.62 (s, 2H), 4.39 (m, 1H), 4.13 (q, 2H) 3.96 (m, 1H),3.68 (s, 2H), 2.56 (m, 2H), 1.28 (m, 6H).

3-(R)-[Benzyl-(1-phenylethyl)-amino]-3-(S)-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)propionic acid ethyl ester (11-7)

To a stirred suspension of NaH (65 mg, 60%, 1.6 mmol) in DMF (5 mL)under argon was added a solution of 11-6 (650 mg, 1.4 mmol) in DMF (10mL) via syringe. This yellow solution was stirred at room temperaturefor 30 minutes. Iodomethane (500 μL, 8.0 mmol) was added and thesolution then stirred at room temperature for an additional 30 minutes.The reaction was quenched with saturated NaHCO₃. The aqueous layer wasextracted three times with CH₂ Cl₂. The combined organic layers werewashed with brine, dried (Na₂ SO₄) and concentrated. Flashchromatography (silica gel; 25:75 EtOAc/hexanes) afforded 11-7 as aclear oil.

TLC Rf=0.6 (25:75 EtOAc/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 7.30 (m, 10H), 7.06 (m, 2H), 6.91 (d, 1H),4.62 (s, 2H), 4.39 (m, 1H), 4.13 (q, 2H) 3.96 (m, 1H), 3.68 (s, 2H),3.35 (s, 3H), 2.56 (m, 2H), 1.26 (m, 6H).

3-(S)-Amino-3-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)propionic acid ethyl ester (11-8)

A stirred solution of 11-7 (581 mg, 1.2 mmol), MeOH (10 mL), AcOH (1.0mL), and H₂ O (0.3 mL) was degassed with argon for 5 minutes. Pd(OH)₂(581 mg) was added and the reaction was placed under 1 atm of H₂ for 2.5h. The reaction was diluted with EtOAc and filtered through celite. Thefiltrate was concentrated to yield 11-8 as a clear oil.

TLC Rf=0.3 (5:95 MeOH/CH₂ Cl₂)

¹ H NMR (300 MHz, CDCl₃) δ 7.04 (m, 2H), 6.93 (dd, 1H), 4.61 (s, 2H),4.39 (m, 1H), 4.13 (q, 2H), 3.37 (b, 2H), 3.35 (s, 3H), 2.69 (m, 2H),1.24 (t, 3H). ##STR23##

2-tert-Butoxycarbonylamino-5-aminopyridine (12-2)

A solution of 2-amino-4-bromopyridine 12-1 (10.1 g, 58.4 mmol) in 150 mLof melted t-BuOH was treated with di-tert-butyl dicarbonate (14.0 g,64.2 mmol). After the solution was stirred for 12 hr, the solvent wasevaporated. The residue was purified using silica gel flashchromatography (CHCl₃ /hexanes, 5:1) to afford the desired product 12-2as a solid.

Rf (silica, 100% CHCl₃)=0.56

¹ H NMR (300 MHz, CDCl₃) δ 8.82 (bs, 1H), 8.38 (d, 1H), 8.78 (d, 1H),7.78 (dd, 1H), 1.55 (s, 9H).

2-(tert-Butoxycarbonyl-methyl-amino)-5-aminopyridine (12-3)

To a solution of 12-2 (6.0 g, 22.0 mmol) in 50 mL DMF at 0° C. was addedNaH gradually. After the mixture was stirred for 40 min, CH₃ I (3.4 g,24.0 mmol) was added in one portion. The reaction mixture was stirredfor 5 hr, treated with 300 mL water and extracted three times with ethylether. The combined organic layers were washed with brine and dried overNa₂ SO₄. After solvent removal, the residue was purified by silica gelflash chromatography (CHCl₃ /hexanes 6:1) to afford the desired product12-3 as a solid.

Rf (silica, 100% CHCl₃)=0.40

¹ H NMR (300 MHz, CDCl₃) δ 8.40 (dd, 1H), 7.68 (m, 2H), 3.36 (s, 3H),1.55 (s, 9H).

3-[6-(tert-Butoxycarbonyl-methyl-amino)-pyridin-3-yl]-acrylic acid ethylester (12-4)

A mixture of 12-3 (6.0 g, 20.9 mmol), ethyl acrylate (6.3 mL, 62.7mmol), triethylamine (17 mL, 125.5 mmol), tri-o-tolylphosphine (1.3 g,6.2 mmol) and Pd(OAc)₂ (0.5 g, 2.1 mmol) in 50 mL CH₃ CN was purged withargon for 5 min and subsequently refluxed at 110° C. for 20 hr. Themixture was cooled and concentrated. The residue was purified usingsilica gel flash chromatography (EtOAc/hexanes 1:3) to afford thedesired product 12-4 as an oil.

¹ H NMR (300 MHz, CDCl₃) δ 8.47 (bs, 1H), 7.82 (m, 2H), 7.64 (d, 1H),6.42 (d, 1H), 4.27 (q, 2H), 3.43 (s, 3H), 1.54 (s, 9H), 1.34 (t, 3H).

3-Benzylamino-3-[6-(tert-butoxycarbonyl-methyl-amino)-pyridin-3-yl]-propionicacid ethyl ester (12-5)

A mixture of 12-4 (1.7 g, 5.6 mmol) and benzylamine (8 mL, 73.2 mmol)was heated in a sealed-tube at 95° C. for 24 hr. The crude reactionmixture was purified using silica gel flash chromatography(EtOAc/hexanes 1:3 to 1:1) to afford the desired product 12-5 as an oil.Rf (silica, EtOAc/hexanes 1:1)=0.63.

3-Amino-3-[6-(tert-butoxycarbonyl-methyl-amino)--pyridin-3-yl]-propionicacid ethyl ester (12-6)

A mixture of 12-5 (1.5 g 3.6 mmol), 20% Pd(OH)₂ /C (0.3 g), AcOH (5.5mL) and EtOH (50 mL) was purged with argon 3 times under vacuum. Thereaction mixture was stirred under balloon hydrogenation condition for16 hr and filtered through a celite pad. After solvent removal, thedesired product 12-6 was obtained as the acetate salt.

¹ H NMR (300 MHz, CDCl₃) δ 8.38 (d, 1H), 7.70 (m, 2H), 4.50 (dd, 1H),4.15 (q, 2H), 3.40 (s, 3H), 2.80 (m, 2H), 1.25 (t, 3H). ##STR24##

3-(2-Fluoro-biphenyl-4-yl)-acrylic acid ethyl ester (13-2)

A solution of 2-fluoro-4-bromobiphenyl 13-1 (7.5 gm, 31.8 mmol), ethylacrylate (4.3 mL), Pd(OAc)₂ (0.714 gm, 3.2 mmol), tri-o-tolylphosphine(1.94 gm, 1.5 mmol) and triethylamine (12 mL) was heated to 100° C. in asealed tube for 12 h. The reaction was cooled to room temperature anddiluted with dichloromethane (40 mL). The organic solution was washedwith 10% aq. citric acid (20 mL), satd. aq. NaHCO₃, and brine (20 mL).The organic solution was dried over MgSO₄, filtered, and concentrated.The residue was purified by flash chromatography (95:5 to 90:10hexanes/EtOAc) to give the acrylate ester 13-2 as a white solid.

TLC Rf=0.44 (10% ethyl acetate/hexanes).

3-[Benzyl-(1(R)-phenylethyl)-amino]-3-(2-fluoro-bi henyl-4-yl)-propionicacid ethyl ester (13-3)

A cooled (0° C.) solution of N-benzyl-(R)-α-methylbenzylamine (8.9 mL,42.6 mmol) in THF (100 mL) was treated with n-butyllithium (26.6 mL of a1.6 M soln in hexanes; 42.6 mmol). After stirring for 10 min, the purplesolution was cooled to -78° C. and treated with a solution of ester 13-2(5.76 g, 21.3 mmol) in THF (10 mL). After stirring for 20 min, thesolution was quenched with satd aq NH₄ Cl soln (5 mL), and the cold bathremoved. The reaction mixture was diluted with Et₂ O (100 mL), andwashed with 10% aq citric acid (50 mL), satd aq NaHCO₃ (50 mL), 5% aqacetic acid (30 mL), 10% aq K₂ CO₃ (50 mL), and brine (50 mL). Thesolution was dried over MgSO₄, filtered and concentrated. The residuewas purified by flash chromatography (90:10 hexanes/EtOAc) to giveadduct 13-3.

TLC Rf=0.48 (10% ethyl acetate/hexanes).

3-Amino-3-(2-fluoro-biphenyl-4-yl)-propionic acid ethyl ester (13-4)

A solution of the dibenzylamine 13-3 (5.65 gm, 11.75 mmol) in EtOH/HOAc(90/10 mL) was purged with argon and treated with Pd(OH)₂ (3 g) andplaced under 1 atm of H₂ gas for 12 h. Additional portions (2.5 g) orPd(OH)₂ were added after 24 h, 48 h and 144 h. The reaction mixture waspurged with argon, filtered through Celite, and the filtrate dissolvedin aq HCl (pH=1). The aqueous solution was washed with EtOAc,neutralized with satd aq NaHCO₃, and extracted with EtOAc (3×30 mL). Thecombined organic solutions were washed with brine, dried over MgSO₄,filtered and concentrated to give the desired product 13-4.

¹ H NMR (300 MHz, CD₃ OD) δ 7.41 (m, 8H), 4.10 (m, 1H), 4.06 (m, 2H),2.73 (m, 2H), 1.18 (m, 3H) ppm. ##STR25##

3-(3-Hydroxy-4-nitro-phenyl)-acrylic acid ethyl ester (14-2)

To a solution of aldehyde 14-1 (15.0 g, 98.0 mmol) in CH₂ Cl₂ (300 mL)was slowly added carboethoxymethylenetriphenylphosphorane (34.1 g, 98.0mmol). The orange solution was stirred for 12 h at ambient temperature.The solution was concentrated to a paste and purified by flashchromatography (10% EtOAc/CH₂ Cl₂) to give 14-2 as a yellow solid.

TLC Rf=0.51 (30% ethyl acetate/hexanes).

¹ H NMR (300 MHz, CD₃ OD) δ 8.08 (d, J=8.4 Hz, 1H), 7.63 (d, J=16.2 Hz,1H), 7.35 (d, J=1.5 Hz, 1H), 7.27 (dd, J=8.4, 1.5 Hz, 1H), 6.65 (d,J=15.9 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 1.32 (t, J=6.9 Hz, 3H) ppm.

3-(2-Oxo-2,3-dihydro-benzoxazol-6-yl)-acrylic acid ethyl ester (14-3)

To a solution of the nitrophenol 14-2 (12.0 g, 57.4 mmol) in warm (70°C.) AcOH/H₂ O (200 mL) was added iron dust (9.61 g, 172.2 mmol). Thebrown heterogeneous mixture was stirred for 30 min at 70-80° C. Themixture was filtered hot through Celite, and the Celite bed washed withEtOAc (2×200 mL). The filtrate was cautiously neutralized with satd aqNaHCO₃ (3×100 mL). The solution was dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography (5% MeOHin CH₂ Cl₂) give an orange solid (9.6 g, 81%). A portion of this solid(4.5 g, 21.7 mmol) was dissolved in THF (150 mL) and treated with1,1-carbonyldiimidazole (3.87 g, 23.8 mmol) and the solution was stirredat ambient temperature for 24 h. The solution was diluted with EtOAc(100 mL) and washed with 10% HCl (50 mL) and brine (50 mL). The solutionwas dried over MgSO₄, filtered, and concentrated. The residue waspurified by flash chromatography (5% MeOH in CH₂ Cl₂) to give 14-3 as ayellow solid.

TLC Rf=0.49 (5% MeOH/CH₂ Cl₂).

¹ H NMR (300 MHz, CD₃ OD) δ 7.77 (d, J=15.9 Hz, 1H), 7.55 (s, 1H), 7.41(d, J=8.4 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 6.47 (d, J=15.9 Hz, 1H), 4.22(q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H) ppm.

3S-Amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-propionic acid ethylester (14-4)

A solution of N-benzyl-α-(R)-methylbenzylamine (4.08 g, 19.3 mmol) inTHF (120 mL) at 0° C. was treated with n-BuLi (7.72 mL of a 2.5 M solnin hexanes). The resulting solution was stirred at 0° C. for 30 min andthen cooled to -78° C. A solution of acrylate 14-3 (1.5 g, 6.43 mmol) inTHF (20 mL) was added. After stirring for 15 min at -78° C., satd aq NH₄Cl soln (25 mL) was added and the cold bath removed. The mixture waswarmed to room temperature, and extracted with Et₂ O (2×40 mL). Thecombined organic extracts were washed with brine (30 mL), dried overMgSO₄, filtered, and concentrated. The residue was purified by flashchromatography (30% ethyl acetate/hexanes) to give 2.74 g of theβ-aminoester as a yellow oil. The aminoester was dissolved in EtOH/H₂O/AcOH (54 mL/4.8 mL/1.2 mL), degassed with argon, and treated withPd(OH)₂ (2.74 g). The mixture was placed under 1 atm of H₂. Afterstirring for 18 h, the mixture was diluted with EtOAc, and filteredthrough Celite. The filtrate was concentrated to give ester 14-4 as anoff-white solid.

TLC Rf=0.10 (5% MeOH/CH₂ Cl₂).

¹ H NMR (300 MHz, CD₃ OD) δ 7.34 (s, 1H), 7.26 (dd, J=1.2, 8.1 Hz, 1H),7.12 (d, J=8.1 Hz, 1H), 4.65 (t, J=7.2 Hz, 1H), 4.13 (q, J=6.9 Hz, 2H),2.98 (m, 2H), 1.20 (t, J=7.2 Hz, 3H) ppm. ##STR26##

3-(4-Hydroxy-3-fluorophenyl)-acrylic acid ethyl ester (15-2)

A solution of 2-fluoro-4-bromophenol 15-1 (50 g, 261.8 mmol), ethylacrylate (34 mL), Pd(OAc)₂ (2.5 g), tri-o-tolylphosphine (5 g) andtriethylamine (83 mL) was heated to 100° C. in a sealed tube for 12 h.The reaction was cooled to room temperature and diluted withdichloromethane (100 mL). The organic solution was washed with 10% aq.citric acid (40 mL), satd aq NaHCO₃, and brine (40 mL). The organicsolution was dried over MgSO₄, filtered and concentrated. The residuewas purified by flash chromatography (50:50 hexanes/EtOAc to 100% EtOAc)to give acrylic acid 15-2 as a white solid.

TLC Rf=0.45 (50% ethyl acetate/hexanes).

3-[Benzyl-(1(R)-phenylethyl)-amino]-3-(4-ethoxy-3-fluorophenyl)-propionicacid ethyl ester (15-4)

To a stirred solution of 15-2 (49.25 gm, 234.5 mmol) in DMF (600 mL) wasadded Cs₂ CO₃ (84.1 gm, 257.9 mmol) and ethyl iodide (18.8 mL, 234.5mmol). After stirring for 12 h at room temperature, the reaction mixturewas diluted with EtOAc (1L) and Washed with water (6×300 mL), 10% aq.citric acid (200 mL), satd. aq. NaHCO₃ (200 mL), and brine (300 mL). Theorganic solution was dried over MgSO₄, filtered, and concentrated togive 52.9 g (95%) of the product 15-3 as an orange oil whichcrystallized upon standing. A cooled (0° C.) solution ofN-benzyl-(R)-α-methylbenzylamine (71 mL, 339.4 mmol) in THF (650 mL) wastreated with n-butyllithium (212 mL of a 1.6 M soln in hexanes; 339.4mmol). After stirring for 10 min, the purple solution was cooled to -78°C. and treated with a solution of ester 15-3 (53.8 g, 226.3 mmol) in THF(100 mL). After stirring for 20 min, the solution was quenched with satdaq NH₄ Cl soln (50 mL), and the cold bath removed. The reaction mixturewas diluted with Et₂ O (1000 mL), and washed with 10% aq citric acid(300 mL), satd aq NaHCO₃ (300 mL), 5% aq acetic acid (300 mL), 10% aq K₂CO₃ (300 mL), and brine (200 mL). The solution was dried over MgSO₄,filtered and concentrated. The residue was purified by flashchromatography (85:15 hexanes/EtOAc) to give the adduct 15-4.

TLC Rf=0.39 (25% ethyl acetate/hexanes).

3-Amino-3-(4-Ethoxy-3-fluorophenyl)-propionic acid ethyl ester (15-5)

A solution of the dibenzylamine 15-4 (30.0 gm, 66.8 nmmol) in EtOH/HOAc(340/30 mL) was purged with argon and treated with Pd(OH)₂ (6 g) andplaced under 1 atm of H₂ for 12 h. Additional portions (2.5 g) ofPd(OH)₂ were added after 24 h and 48 h. The reaction mixture was purgedwith argon, filtered through Celite, and the filtrate collected. Thefiltrate was concentrated to yield the desired amine 15-5.

¹ H NMR (300 MHz, CD₃ OD) δ 7.19 (m, 3H), 4.62 (m, 1H), 4.07 (m, 4H),2.99 (m, 2H), 1.39 (m, 3H) 1.18 (m, 3H) ppm. ##STR27##

5-Ethoxy-nicotinic acid ethyl ester (16-2)

A mixture of 3-hydroxy-nicotinic acid methyl ester 16-1 (15 g, 90.8mmol), ethyl iodide (14.5 ml, 181.6 mmol), cesium carbonate (29.5 g,90.8 mmol) and DMF (150 mL) was stirred at ambient temperature for 3hours. The reaction mixture was diluted with Et₂ O and then washed with10% K₂ CO₃, brine, dried (MgSO₄), and concentrated to give the ester16-2 as a red oil.

TLC R_(f) =0.52 (silica,75% EtOAc/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 8.82 (s, 1H), 8.46 (s,1H), 7.75 (s, 1H), 4.40(q, 2H, J=7Hz), 4.12 (q, 2H, J=7Hz), 1.43 (m, 6H).

5-Ethoxy-N-methoxy-N-methyl-nicotinamide (16-3)

To a solution of 16-2 (15 g, 72 mmol) in EtOH (100 mL) was added 1N NaOH(80 ml, 80 mmol). After stirring for 1 h, the solvents were evaporatedand the residue was dissolved in 1N HCl (80 ml, 80 mmol) and thenconcentrated, azeotroped with CH₃ CN to give the crude acid. The crudeacid was suspended in DMF (200 mL) and then treated with HCl.HN(Me)OMe(13.9 g, 144 mmol), EDC (15.1 g, 79.2 mmol), HOBT (9.6 g, 72 mmol) andNMM (60 mL, 576 mmol). The mixture was stirred for 18 hours and thenconcentrated. The residue was dissolved in ethyl acetate, washed with10% K₂ CO₃, brine, dried (MgSO₄), and concentrated to give amide 16-3 asa brown oil.

TLC R_(f) =0.30 (silica, 70:25:5 chloroform/ ethyl acetate/ MeOH)

5-Ethoxy-pyridine-3-carbaldehyde (16-4)

To a stirred solution of 16-3 (14.0 g, 66.5 mmol) and CH₂ Cl₂ (200 mL)at -78° C. under argon was added DIBAL (1.0M hexanes, 90 ml) dropwiseover 30 minutes. After 30 minutes, the solution was warmed to 0° C. for1 hour. The reaction was quenched with 100 ml 1.0M Rochelle's salt,stirred for 1.0 hour and then extracted with Et₂ O. The organic layerwas dried (MgSO₄), and then concentrated to give the aldehyde 16-4 as abrown oil.

TLC R_(f) =0.32 (silica, 70:25:5 chloroform/ethyl acetate/MeOH)

¹ H NMR (300 MHz, CDCl₃) δ 10.10 (s, 1H),8.65 (s,1H), 8.55 (s,1H), 7.59(s, 1H), 4.14 (q, 2H, J=7Hz), 1.43 (t, 3H, J=7Hz).

3-(5-Ethoxy-pyridin-3-yl)-acrylic acid tert-butyl ester (16-6)

A mixture of 16-4 (8.0 g, 51.6 mmol), 16-5 (20 g, 54.2 mmol), andbenzene (150 mL) was heated to reflux for 30 minutes. The mixture wasdiluted with Et₂ O and then washed with 10% K₂ CO₃, brine and dried(MgSO₄). Following evaporative removal of the solvent, the residue waschromatographed (silica gel, 30% EtOAc/hexanes) to give 16-6 as a yellowsolid.

TLC R_(f) =0.41 (silica, 70:25:5 chloroform/ ethyl acetate/ MeOH)

¹ H NMR (300 MHz, CDCl₃) δ 8.31 (m, 2H),7.55 (d, 1H, J=16Hz), 7.27 (s,1H), 6.40 (d, 1H, J=16Hz), 4.10 (q, 2H, J=7Hz), 1.54 (s,- 9H), 1.44 (m,3H).

3(S)-Amino-3-(5-ethoxy-pyridin-3-yl)-propionic acid tert-butyl ester(16-8)

To a stirred solution of 16-7 (500 mg, 2.38 mmol) and THF at 0° C. wasadded nBuLi (2.5 M THF, 0.95 ml) dropwise. After 20 minutes, thesolution was cooled to -78° C. and 16-6 (500 mg, 1.98 mmol), dissolvedin 3 ml THF, was added. After 15 minutes, the reaction was quenched withsat. NH₄ Cl followed by the removal of the cooling bath. The solutionwas extracted with ethyl acetate. The organic portion was washed withbrine, dried (MgSO₄) and concentrated. The residue was dissolved inacetic acid (14 ml) and the solution was purged with argon for 30minutes. 10% Pd/C (1.0 g) was added and the mixture was heated to 80° C.1,4-Cyclohexadiene (6 ml) was added dropwise maintaining an internaltemperature between 80° C. and 90° C. After 5.0 hours, the mixture wasfiltered through a celite pad, concentrated and then azeotroped withtoluene. The residue was chromatographed (silica gel, 5% [10:10:1EtOH/NH₄ OH/H₂ O]/70:25:5 chloroform/ethyl acetate/MeOH) to give 16-8 asa yellow solid.

¹ H NMR (300 MHz, CDCl₃) δ 8.18 (m, 2H),7.25 (s,1H,), 4.41 (m,1H,), 4.08(q, 2H, J=7Hz), 2.59 (m, 2H,), 1.87 (s, 2H), 1.40 (m, 12H). ##STR28##

3(S)-Amino-3-(5-methoxy-pyridin-3-yl)-propionic acid tert-butyl ester(17-2)

3-Bromo-5-methoxy-pyridine 17-1 (prepared as described in J. Org. Chem.1990, 55, 69) was converted into 17-2 utilizing the procedure describedfor the conversion of 19-2 to 19-5. ¹ H NMR (300 MHz, CD₃ OD) δ 8.20 (d,1H, J=3Hz), 8.18 (d, 1H, J=2Hz),7.50 (s, 1H,), 4.51 (m,1H,), 3.90 (s,3H), 2.87 (m, 2H,), 1.37 (m, 9H). ##STR29##

3-Amino-pent-4-enoic acid ethyl ester (18-2)

A mixture of 5% Pd/BaSO₄ (0.025 g) and quinoline (0.30 mL) was stirredunder a balloon of hydrogen for 30 minutes. 3-Amino-pent-4-ynoic acidethyl ester (18-1) (for preparation, see J. A. Zablocki, et al., J. Med.Chem., 1995, 38, 2378-2394) (1.77 g, 10.0 mmol) in EtOH (15 mL) wasadded and the solution stirred for an additional 2.5 hours. The solutionwas filtered through a pad of celite and concentrated in vacuo toprovide 2.65 g of crude product 18-2. ¹ H NMR (CDCl₃, 300 MHz): δ8.40-7.60 (br s, 2H), 6.11-5.96 (m, 1H), 5.58-5.53 (d, 1H), 5.44-5.41(d, 1H), 4.31-4.16 (m, 3H), 3.12-2.86 (m, 2 H), 1.29-1.25 t, 3H).##STR30##

5-Bromo-2-methoxypyridine (19-2)

To a solution of KOH (4.2 g, 0.075 mol) in water (750 mL) was added2-methoxypyridine 19-1 (16.4 g, 0.15 mol) followed by a dropwiseaddition of bromine (24 g, 0.15 mol) in 1N aqueous KBr (750 mL) and theresulting solution was stirred at room temperature for 5 hr. SolidNaHCO₃ was added until basic and the solution was extracted with CHCl₃(3×500 mL). The organic layer was washed with 10% NaHSO₃, then brine,dried over Na₂ SO₄, filtered and the solvent removed in vacuo. Theresulting dark brown oil was predominantly the desired compound 19-2 andwas used as such in the next step.

¹ H NMR (300 MHz, CDCl₃) δ 3.91 (3H, s), 6.66 (1H, d), 7:.62 (1H, dd),8.20 (1H, d).

Ethyl 3-(6-methoxypyridin-3-yl)acrylate (19-3)

A solution of the 5-bromo-2-methoxypyridine 18-2 (74.3 g, 0.4 mol),ethyl acrylate (150 mL, 1.4 mol), triethylamine (150 mL, 1.08 mol),palladium acetate (10 g, 0.045 mol) and tri-o-tolylphosphine (20 g,0.066 mol) in 100 mL acetonitrile was degassed with argon for 10minutes. The mixture was heated at 90° C. for 12 hr then the volatileswere removed in vacuo. Toluene (300 mL) was added and the mixtureconcentrated again. Diethyl ether (300 mL) was added and the mixturefiltered through a pad of silica gel eluting with 800 mL of diethylether. After removal of the diethyl ether, the residue waschromatographed on silica gel eluting with EtOAc/hexane, 1:19 then 1:14then 1:9, to give 19-3 as a yellow solid.

¹ H NMR (300 MHz, CDCl₃) δ 1.34 (3H, t), 3.97 (3H, s), 4.26 (2H, q),6.34 (1H, d),6.76 (1H, d), 7.63 (1H, d), 7.77 (1H, dd),8.27 (1H, d).

N-Benzyl-(R)-α-methylbenzyl-3(S)-(6-methoxypyridin-3-yl)-β-alanine ethylester (19-4)

To a solution of N-benzyl-(R)-α-methylbenzylamine (97.5 g, 462 mmol) inTHF (750 mL) at 0° C. was added n-butyllithium (2.5M in hexanes; 178.5mL, 446 mmol). The dark violet solution was stirred at 0° C. for 20minutes, cooled to -78° C. and the ester 19-3 (63.7 g, 308 mmol) in THF(250 mL) was added over 60 minutes. The resulting solution was stirredat -78° C. for 1 hr then cannulated into saturated NH₄ Cl and extractedwith EtOAc, washed with water then brine, dried and concentrated invacuo to give an oil. Column chromatography (silica gel; hexane/EtOAc,9:1 then 4:1) gave 19-4 as an oil contaminated withN-benzyl-(R)-α-methylbenzylamine . This oil was taken up in 5% AcOH inwater and extracted with diethyl ether (4×). The organic layers weredried over MgSO₄ and the solvent removed to give the title compound19-4.

¹ H NMR (300 MHz, CDCl₃) δ 1.08 (3H, t), 1.27 (3H, d), 2.52 (1H, dd),2.62 (1H, dd), 3.66 (1H, d), 3.70 (1H, d), 3.93 (3H, s), 3.95 (2H, m),4.41 (1H, dd), 6.74 (1H, d), 7.15-7.45 (10H, m), 7.64 (1H, dd), 8.15(1H, d).

3(S)-(2-methoxypyrid-5-yl)-β-alanine ethyl ester (19-5)

To a degassed (argon) solution of the ester 19-4 (70 g) in EtOH (250mL), HOAc (25 mL) and water (2 mL) was added 20% Pd(OH)₂ on carbon. Themixture was placed under hydrogen gas using a balloon and the resultingmixture was stirred for 24 hr. After filtration through celite (washingwith EtOAc), the solvent was removed in vacuo to afford a waxy solid.This was dissolved in 200 mL water and extracted with diethyl ether(2×200 mL). The aqueous layer was then treated with solid K₂ CO₃ untilfully saturated and extracted with 4×200 mL EtOAc. After drying overMgSO₄, the solvent was removed in vacuo to give the title compound 19-5as an oil which solidified in the freezer.

¹ H NMR (300 MHz, CDCl₃) δ 1.23 (3H, t), 2.61 (1H, dd), 2.68 (1H, dd),3.92 (3H, s), 4.15 (2H, q), 4.41 (1H, dd), 6.93 (1H, d), 7.62 (1H, dd),8.13 (1H, d). ##STR31##

3-Bromo-6-chloro-5-nitropyridine (20-2)

A suspension of CuCl₂ (3.33 g, 24.8 mmol) in anhydrous CH₃ CN (200 mL)at 65° was treated with tert-butylnitrite (3.13 mL, 26.3 mmol), followedby the dropwise addition of a solution of 20-1 in 60 ml of CH₃ CN. Theresulting mixture was stirred under an argon atmosphere at 65° for 2 hand concentrated at reduced pressure. The residue was partitionedbetween EtOAc (150 mL) and 3% HCl (60 ml), and the organic layer washedsuccessively with 3% HCl, water, and brine (60 mL), then dried, filteredand concentrated to afford a brown solid which was chromatographed onsilica (25% EtOAc/Hexane) to afford 20-2 as a yellow crystalline solid.

TLC Rf=0.60 (25% EtOAc/Hexane)

¹ H NMR (300 MHz, CDCl₃) δ 8.70 (d, J=2.4 Hz, 1H), 8.37 (d, J=2.4 Hz,1H).

(3-Nitro-5-bromo-pyridin-2-yloxy)-acetic acid methyl ester (20-3)

Methyl glycolate (450 mg, 5.05 mmol) was added to a suspension of 60%NaH (131 mg, 55 mmol) in THF (20 mL) at 0°. The resulting solution wasstirred under argon for 0.5 hl, then treated with a solution of 20-2.After stirring at 0° for 0.5 h, the reaction was diluted with ethylacetate, and washed with successively with sat. NaHCO₃, water and brine(80 mL each), then dried, filtered and concentrated to afford 20-3 as ayellow solid.

TLC Rf=0.70 (25% EtOAcl Hexane)

¹ H NMR (300 MHz, CDCl₃) δ 8.46 (d, J=2.4 Hz, 1H), 8.37 (d, J=2.4 Hz,1H) 5.15 (s, 2H), 3.78 (s, 3H).

2-Oxo-2,3-dihydro-1H-4-oxa-1,5-diaza-7-bromo-naohthalene (20-4)

A mixture of 20-3 (1.5 g, 5.12 mmol) and powdered tin (1.37 g, 11.5mmol) was treated with conc. HCl (10 mL). The mixture was heated to 80°for 2 h, then cooled and concentrated. The residue was partitionedbetween CHCl₃ and sat. NaHCO₃, washed with brine, then dried, filteredand concentrated to afford a yellow solid. Chromatography on silica gel(50% hexane/EtOAc) gave 20-4 as a yellow solid.

TLC Rf=0.65 (50% EtOAc/Hexane)

¹ H NMR (300 MHz, DMSO-d₆) δ 10.81 (br,s, 1H), 7.88 (d, J=2.4 Hz, 1H),7.25 (d, J=2.4 Hz, 1H), 4.81 (s, 2H).

3-(2-Oxo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl)-acrylic acidtert-butyl ester (20-5)

A mixture of 20-4 (1.12 g, 4.89 mmol), (o-tol)₃ P (298 mg, 1.0 mmol),Pd(OAc)₂ (110 mg, 0.49 mmol), and triethylamine (0.86 mL, 5.87 mmol) inDMF (20 mL) was placed in a 100-mL flask. The mixture was degassed withargon, then tert-butyl acrylate (752 mg, 5.87 mmol) was added and thetube sealed and heated to 100° for 12 h. The reaction mixture wasdiluted with ethyl acetate, filtered and washed with NaHCO₃, water, andbrine, dried, filtered and concentrated. Chromatography on silica gel(25% hex/EtOAc) gave 20-5 as a yellow solid.

TLC Rf=0.60 (25% EtOAc/Hexane)

¹ H NMR (300 MHz, DMSO-d₆) δ 10.91 (br,s, 1H), 8.15 (d, J=2.4 Hz, 1H),7.54 (d, J=16 Hz, 1 H), 7.42 (d, J=2.4 Hz, 1H), 6.35 (d, J=16 Hz, 1 H),4.84 (s, 2H), 1.48 (s, 9H).

3(S)-[Benzyl-(1(R)-phenylethyl)-amino]-3-(2-oxo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl)-propionicacid tert-butl ester (20-6)

A solution of N-benzyl-α-(R)-methylbenzylamine (0.82 g, 3.87 mmol) inTHF (25 mL) at 0° C. was treated with n-BuLi (1.6 mL of a 2.5 M soln inhexanes). The resulting solution was stirred at 0° C. for 30 min andthen cooled to -78° C. A solution of acrylate 20-5 (0.485 g, 1.76 mmol)in THF (5 mL) was added. After stirring for 15 min at -78° C., satd aqNH₄ Cl soln (5 mL) was added and the cold bath removed. The mixture waswarmed to room temperature, and extracted with Et₂ O (2×40 mL). Thecombined organic extracts were washed with brine (30 mL), dried overMgSO₄, filtered, and concentrated. The residue was purified by flashchromatography (40% ethyl acetate/hexanes) to give the β-aminoester 20-6as a yellow oil.

TLC Rf=0.3 (40% ethyl acetate/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 1H NMR 8.70 (br, s, 1H), 7.91 (d, J=1.8 Hz,1H),7.4-7.2 (1OH), 7.12 (d, J=1.8 Hz, 1H), 4.80 (s, 2 H), 4.42 (m, 1H),3.91 (q, J=6.7 Hz, 1 H), 3.69 (d, J=7.2 Hz, 1H, ), 3.62 (d, J =7.2 Hz,1H, ), 2.46 (m, 2H), 1.34 (d, J=7.0 Hz, 3H), 1.29 (s, 9H).

3(S)-Amino-3-(2-oxo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl)-propionic acid tert-butyl ester(20-7)

A mixture of the dibenzylamine 20-6 (0.22 g, 0.44 mmol) in EtOH/H₂O/AcOH (26 mL/3 mL/1.0 mL) was degassed with argon and treated withPd(OH)₂ (100 mg). The mixture was placed under 1 atm of H₂. Afterstirring for 18 h, the mixture was diluted with EtOAc and filteredthrough celite. The filtrate was concentrated and the residue purifiedby flash chromatography (20% 20:1:1 EtOH/NH₄ OH/H₂ O-80% EtOAc) to givethe tert-butyl ester 20-7 as a white solid.

TLC R_(f) =0.5 (20% 20:1:1 EtOH/NH₄ OH/H₂ O - 80% EtOAc)

¹ H NMR (300 MHz, CD₃ OD) δ 7.89 (d, J=1.7 Hz, 1H), 7.31 (d, J=1.7 Hz,1H), 4.81 (s, 2H), 4.38 (m, 1H), 2.6, (m, 2H), 1.41 (s, 9H).

3(R)-[Benzyl-(1-phenylethyl)-amino]-3(S)-(2-thioxo-2,3-dihydro-1H-4-oxa-1.5-diaza-naphthalen-7-yl)-propionicacid tert. butyl ester (20-8)

A solution of 20-6 (0.22 g, 0.44 mmol ) in anhydrous THF was treatedwith Lawesson's reagent (0.098 g, 0.243 mmol) and stirred at roomtemperature for 1.5 h. Silica gel (500 mg) was added to the reactionmixture and the solvent was removed at reduced pressure and the productwas eluted from silica using 25% EtOAc/hex to afford 20-8 as a yellowsolid.

TLC R_(f) =(40% EtOAc/hexane) 0.7

¹ H NMR (300 MHz, CD₃ OD) δ 9.82 (br, s, 1H), 7.95 (d, J=1.8 Hz,1H),7.4-7.2 (11H), 5.08 (s, 2 H), 4.42 (m, 1H), 3.91 (q, J=6.7 Hz, 1 H),3.69(d, J=7.2 Hz, 1H, ), 3.62 (d, J =7.2 Hz, 1H), 2.46 (m, 2H), 1.34 (d,J=7.0 Hz, 3H), 1.29 (s, 9H).

3(S)-Amino-3-(2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl)-propionicacid tert. butyl ester (20-9)

A solution of 20-8 (1.0 g, 1.9 mmol) in anhydrous Et₂ O (10 mL) at 0°was treated dropwise with LiAlH₄ (2.09 ml of a 1.0 M solution in Et₂ O).The resulting solution was stirred at 0° C. for 30 min and then quenchedby the sequential addition of H₂ O(0.3 mL), 15 % NaOH (0.08 mL). Celite(1 g) was added and the mixture filtered through a Celite pad. Thefiltrate was evaporated and the residue was purified by flashchromatography (65% ethyl acetate/hexanes) to give the dibenzylamineintermediate as a yellow oil.

TLC Rf=0.4 (65% ethyl acetate/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 1H NMR 7.61 (d, J=1.8 Hz, 1H),7.4-7.2 (1OH),6.87 (d, J=1.8 Hz, 1H), 4.41 (m, 2 H), 4.36 (m, 1H), 3.91 (q, J=6.7 Hz,1 H), 3.8 (brs, 1H), 3.69 (m, 2H), 3.42 (m, 2H), 2.46 (m, 2H), 1.34 (d,J=7.0 Hz, 3H), 1.29 (s, 9H).

This material was deprotected with Pd(OH)₂ to afford 20-9 as a whitesolid. TLC R_(f) =0.5 (20% 20:1:1 EtOH/NH₄ OH/H₂ O-80% EtOAc)

¹ H NMR (300 MHz, CD₃ OD) δ 7.59 (d, J=1.7 Hz, 1H), 6.92 (d, J=1.7 Hz,1H), 4.41 (m, 2H), 4.30 (m, 1H), ), 3.41 (m, 2H), 2.6, (m, 2H), 1.41 (s,9H). ##STR32##

3-Oxo-3,4-dihydro-2H-1-oxa-4,5-diaza-7-bromo-naphthalene (21-2)

A solution of 21-1 (4.8 g, 32 mmol) in MeOH (160 mL) at -15° was treateddropwise with bromine (25.7 g, 161 mmol). After stirring at -15° for 0.5h, the mixture was warmed to ambient temperature and stirred overnight.The resulting white precipitate was filtered and washed with cold MeOHto afford 21-2 as a white solid.

TLC Rf=0.65 (50% EtOAc/Hexane)

¹ H NMR (300 MHz,DMSO-d₆) d 11.2 (br,s, 1H), 8.05 (d, J=2.4 Hz, 1H),7.66 (d, J=2.4 Hz, 1H), 4.76 (s, 2H).

3(S)-Amino-3-(3-oxo-3 .4-dihydro-2H-1-oxa-4.5-diaza-naphthalen-7-yl)-propionic acid tert-butyl ester (21-3)

Bromide 21-2 was converted to amino ester 21-3 as illustrated in Scheme20.

TLC R_(f) =0.5 (12% 20:1:1 EtOH/NH₄ OH/H₂ O- 88% EtOAc)

¹ H NMR (300 MHz, CD₃ OD) δ 8.04 (d, J=1.7 Hz, 1H), 7.34 (d, J=1.7 Hz,1H), 4.76 (s, 2H), 4.38 (m, 1H), 2.6, (m, 2H), 1.41 (s, 9H).

3(S)-Amino-3-(3-oxo-3,4-dihydro-2H-1-oxa-4,5-diaza-naphthalen-7-yl)-propionicacid tert-butyl ester (21-4)

Bromide 21-2 was converted to amino ester 21-4 as illustrated in Scheme20.

TLC R_(f) =0.5 (20% 20:1:1 EtOH/NH₄ OH/H₂ O- 80% EtOAc)

¹ H NMR (300 MHz, CD₃ OD) δ 8.04 (d, J=1.7 Hz, 1H), 7.34 (d, J=1.7 Hz,1H), 4.76 (s, 2H), 4.38 (m, 1H), 2.6, (m, 2H), 1.41 (s, 9H). ##STR33##

Furo-[2,3-b]-vridine-5-carboxaldehyde (22-2)

A solution of alcohol 22-1 (M. Bhupathy, et al., J. Heterocycl. Chem.1995, 32, 1283-1287) was treated with excess MnO₂ (10 eq) and themixture stirred at room temperature for 16 h, then filtered throughCelite and evaporated to afford 22-2 as a white solid.

TLC Rf=0.40 (25% EtOAc/Hex)

¹ H NMR (300 MHz, CDCl₃) δ 10.22 (s, 1H), 9.05 (d, J=1.8 Hz, 1H), 8.27(d, J=1.7 Hz, 1H) 8.08 (d, J=1.8 Hz, 1H), 7.10 (d, J=1.7 Hz, 1H).

3-Amino-3-(furo[2,3-b]pyridin-5-yl)-propionic acid ethyl ester (22-3)

A solution containing aldehyde 22-2 (1.5 g, 10 mmol), ethyl hydrogenmalonate (1.6 g, 20 mmol), and ammonium acetate (3.8 g, 50 mmol) inanhydrous ethanol (125 mL) was heated at reflux for 8 h. After coolingto room temperature, the solvent was evaporated and the residuepartitioned between sat. sodium bicarbonate and EtOAc, the organic layerremoved, dried, and concentrated. Chromatography of the residue affordedthe amino ester 22-3 as a waxy solid.

TLC R_(f) =0.5 (20% 20:1:1 EtOH/NH₄ OH/H₂ O- 80% EtOAc)

¹ H NMR (300 MHz, CD₃ OD) δ 8.34 (d, J=1.7 Hz, 1H), 8.04 (d, J=1.7 Hz,1H), 7.72 (d, J=1.7 Hz, 1H), 6.78 (d, J =1.7 Hz, 1H), 4.62 (m, 1H), 4.13(q, J=7.5 Hz, 2H), 3.20 (br, s, 2H), 2.76 (m, 2H), 1.23 (t, J=7.5 Hz,3H). ##STR34##

Furo[3.2-b]pyridine-5-carboxaldehyde (23-2)

A solution of alcohol 23-1 (J. M. Hoffinan, Jr., U.S. Pat. No.4,808,595) was treated with excess MnO₂ (10 eq) and the mixture stirredat room temperature for 16 h, then filtered through Celite andevaporated to afford 23-2 as a white solid.

¹ H NMR (300 MHz, CDCl₃) δ 10.18 (s, 1H), 8.92 (d, J=1.8 Hz, 1H), 8.17(d, J=1.7 Hz, 1H) 7.89 (d, J=1.8 Hz, 1H), 7.10 (d, J=1.7 Hz, 1H).

3-Amino-3-(furo[3,2-b]pyridin-5-yl)-propionic acid ethyl ester (23-3)

A solution containing aldehyde 23-2 (1.5 g, 10 mmol), ethyl hydrogenmalonate (1.6 g, 20 mmol), and ammonium acetate (3.8 g, 50 mmol) inanhydrous ethanol (125 mL) was heated at reflux for 8 h. After coolingto room temperature, the solvent was evaporated and the residuepartitioned between sat. sodium bicarbonate and EtOAc, the organic layerremoved, dried, and concentrated. Chromatography of the residue affordedthe amino ester 23-3 as a waxy solid.

TLC R_(f) =0.5 (20% 20:1:1 EtOH/NH₄ OH/H₂ O - 80% EtOAc)

¹ H NMR (300 MHz, CD₃ OD) δ 8.58 (d, J=1.7 Hz, 1H), 7.89 (d, J=1.7 Hz,1H),7.85(d, J- 1.7 Hz, 1H), 6.98 (d, J =1.7 Hz, 1H), 4.62 (t, J=7.2 Hz,1H), 4.09 (q, J=7.5 Hz, 2H), 2.76 (m, 2H), 2.20 (br, s, 2H), 1.21 (t,J=7.5 Hz, 3H). ##STR35##

N-(S)-(2-Amino-phenyl)-3-tert-butoxycarbonylamino-succinamic acid methylester (24-3)

A mixture of Boc-L-aspartic acid-p-methyl ester 24-1 (5.0 g, 20.2 mmol),o-phenylenediamine 24-2 (2.2 g, 20.2 mmol), EDC (3.9 g, 20.2 mmol), HOAT(0.28 g, 2.02 mmol), and NMM (6.7 mL, 60.7 mmol) in DMF (50 mL) wasstirred for 18 h at ambient temperature. The solution was diluted withEtOAc (250 mL) and washed with sat. sodium bicarbonate, water, and brine(50 mL each), then dried and evaporated to afford 24-3 as a yellowsolid.

TLC R_(f) =0.50 (95% CHCl₃ /5% isopropanol)

¹ H NMR (300 MHz, CDCl₃) δ 8.10 (br,s, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.08(t, J=7.8 Hz, 1H)6.78 (m, 1H),5.8 (br d, 1H), 4.65 (m, 1 H), 3.76 (s,3H), 3.15 (dd, J=4.6, 16 Hz, 1H), 2.90 (dd, J=5.1, 16 Hz, 1H), 1.48 (s,9H).

3(S)-Amino-3-Benzimidazol-2-yl-propionic acid methyl ester (24-4)

Ester 24-3 (1.0 g, 3 mmol) was dissolved in acetic acid (50 mL) andheated to 65° for 2 h. The solvent was removed to afford theBoc-protected intermediate as a white solid. The crude material (920 mg,2.43 mmol) was dissolved in EtOAc, cooled to 0°, and treated with HClgas to give 24-4 as a tan solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.80 (m, 2H), 7.35 (m,2H), 5.98 (m, 1H),3.80 (m,. 2H), 3.76 (s, 3H). ##STR36##

N-(S)-(2-Hydroxy-phenyl)-3-tert-butoxycarbonylamino-succinamic acidmethyl ester (25-2)

A mixture of Boc-L-aspartic acid-β-methyl ester (24-1 (5.0 g, 20.2mmol), 2-amino phenol (25-1 (2.2 g, 20.2 mmol), EDC (3.9 g, 20.2 mmol),HOAT (0.28 g, 2.02 mmol), and NMM (6.7 mL, 60.7 mmol) in DMF (50 mL) wasstirred for 18 h at ambient temperature. The solution was diluted withEtOAc (250 mL) and washed with sat. sodium bicarbonate, water, and brine(50 mL each), then dried, and evaporated and chromatographed on silica(EtOAc) to afford 25-2 as a white solid.

TLC R_(f) =0.55 (EtOAc))

¹ H NMR (300 MHz, CDCl₃) δ 7.23 (d, J=7.8 Hz, 1H), 6.89 (t, J=7.8 Hz,,1H), 6.78 (m, 1H), 5.68 (b,r d, 1H), 4.65 (m, 1 H), 3.76 (s, 3H), 3.15(dd, J=4.6, 16 Hz, 1H), 2.90 (dd, J=5.1, 16 Hz, 1H), 1.48 (s, 9H).

3(S)-Amino-3-Benzoxazol-2-yl-propionic acid methyl ester (25-3)

Ester 25-2 (2.0 g, 6.0 mmol) was dissolved in anhydrous THF (150 mL)along with Ph₃ P (1.58 g, 6.0 mmol). The resulting solution was cooledto 0°, and a solution of diethyl azodicarboxylate (1.53 g, 6.2 mmol) inTHF (25 mL) was added dropwise. The cooling bath was removed and thesolution stirred overnight at ambient temperature. The solution wasconcentrated and the residue chromatographed (75% EtOAc/Hexane) toafford the Boc-protected ester as a colorless glass. The crude material(1.8 g, 5.0 mmol) was dissolved in EtOAc, cooled to 0° and treated withHCl gas to give 25-3 as a tan solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.81 (m, 2H), 7.40 (m,2H), 5.05 (t, J=7.4Hz, 1H), 3.72 (s, 3H), 3.30 (m, 2H). ##STR37##

1-Methyl-4-bromopyrazole (26-2)

Methyl iodide (8.47 mL, 136 mmol) was added to a mixture of4-bromopyrazole 26-1 (10 g, 38 mmol), and K₂ CO₃ (18.9 g, 136 mmol) inCH₃ CN (150 mL) and the mixture stirred at room temperature for 16 h,then filtered and evaporated to yield 26-2 as a yellow oil.

¹ H NMR (300 MHz, CDCl₃) δ 7.44(s, 1H),7.38 (s, 1H), 3.90 (s, 3H).

3 (S)-Amino-3-(1-methyl-1H-pyrazol-4-yl)-propionic acid ethyl ester(26-3)

The bromide 26-2 was converted to the amino ester 26-3 following theprocedure depicted in Scheme 19.

¹ H NMR (300 MHz, CD₃ OD) δ 7.81 (s, 1H),7.58 (s, 1H),4.80 (m, 1H), 4.05(q, J=7.0 Hz, 2 H), 3.89 (s, 3H), 3.00 (m, 2 H), 1.24 (t, J =7.0 Hz, 3H).

Additional examples of the present invention are listed below and can beprepared by the method shown in Scheme 2 using in place of 1-4 thevarious 3-substituted β-alanine derivatives prepared according to theprocedures depicted in Schemes 9-26 above. These examples can beprepared in high optical purity substituting intermediate 7-5 or itsenantiomer for intermediate 2-5.

3(S)-(6-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(6-Amino-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(4-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3-(6-Methylamino-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(2-Fluoro-biphenyl-4-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(2-Oxo-2,3-dihydro-benzoxazol-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(4-Ethoxy-3-fluorophenyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(5-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(5-Methoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(Ethynyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(6-Methoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(2-Oxo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(2,3-Dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl)-3-:(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(2-Oxo-3,4-dihydro-2H-1-oxa-4,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(3,4-Dihydro-2H-1-oxa-4,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3-(Furo-[2,3-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3-(2,3-Dihydrofuro[2,3-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3-(Furo-[3,2-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3-(2,3-Dihydrofuro[3,2-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(Benzimidazol-2-yl)3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(1H-Imidazo[4,5-c]pyridin-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(Benzoxazol-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;

3(S)-(1-Methyl-1H-pyrazol-4-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid; and

3(S)-{2-Oxo-3-[3-t5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl}-pent-4-enoicacid. ##STR38##

N-(4-Iodo-phenylsulfonylamino)-L-asparazine (A-2)

To a stirred solution of acid A-1 (4.39 g, 33.2 mmol), NaOH (1.49 g,37.2 mmol), dioxane (30 ml) and H₂ O (30 ml) at 0° C. was added pipsylchloride (10.34 g, 34.2 mmol). After ˜5 minutes, NaOH (1.49, 37.2 mmol),dissolved in 15 ml H₂ O, was added followed by the removal of thecooling bath. After 2.0 h, the reaction mixture was concentrated. Theresidue was dissolved in H₂ O (300 ml) and then washed with EtOAc. Theaqueous portion was cooled to 0° C. and then acidified with concentratedHCl. The solid was collected and then washed with Et₂ O to provide acidA-2 as a white solid.

¹ H NMR (300 MHz, D₂ O) δ 7.86 (d, 2H, J=8Hz ), 7.48 (d, 2H, J=8Hz) 3.70(m, 1H), 2.39 (m, 2H).

2(S)-(4-Iodo-phenylsulfonylamino)-β-alanine (A-3)

To a stirred solution of NaOH (7.14 g, 181.8 mmol) and H₂ O (40 ml) at0° C. was added Br₂ (1.30 ml, 24.9 mmol) dropwise over a ten minuteperiod. After ˜5 minutes, acid A-2 (9.9 g, 24.9 mmol), NaOH (2.00 g,49.8 mmol) and H₂ O (35 ml) were combined, cooled to 0° C. and thenadded in a single portion to the reaction. After stirring for 20 minutesat 0° C., the reaction was heated to 90° C. for 30 minutes and thenrecooled to 0° C. The pH was adjusted to ˜7 by dropwise addition ofconcentrated HCl. The solid was collected, washed with EtOAc, and thendried in vacuo to provide acid A-3 as a white solid.

¹ H NMR (300 MHz, D₂ O) δ 8.02 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz), 4.36(m, 1H), 3.51 (dd, 1H, J=5Hz, 13Hz) 3.21 (m, 1H).

Ethyl 2(S)-(4-iodo-phenylsulfonylamino)-β-alanine-hydrochloride (A-4)

HCl gas was rapidly bubbled through a suspension of acid A-3 (4.0 g,10.81 -mmol) in EtOH (50 ml) at 0° C. for 10 minutes. The cooling bathwas removed and the reaction was heated to 60° C. After 18 h, thereaction was concentrated to provide ester A-4 as a white solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.98 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz),4.25 (q, 1H, J=5Hz), 3.92 (m, 2H), 3.33 (m, 1H), 3.06 (m, 1H), 1.01 (t,3H, J=7Hz).

Ethyl 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoate (A-5a)

A mixture of ester A-5 (700 mg, 2.63 mmol), (for preparation, see:Scheme 29 of PCT International Application Publication No. WO 95/32710,published Dec. 7, 1995) 10% Pd/C (350 mg) and EtOH were stirred under 1atm H₂. After 20 h, the reaction was filtered through a celite pad andthen concentrated to provide ester A-5a as a brown oil.

TLC R_(f) =0.23 (silica, 40% EtOAc/hexanes)

¹ H NMR (300 MHz, CDCl₃) δ 7.95 (d, 2H, J=8Hz), 7.26 (m, 3H), 6.43 (d,1H, J=7Hz), 6.35 (d, 1H, J=8Hz), 4.37 (m, 4H), 3.05 (m, 2H), 2.91 (m,2H), 1.39 (t, 3H, J=7Hz).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoic acid hydrochloride (A-6)

A suspension of ester A-5a (625 mg, 2.31 mmol) in 6N HCl (12 ml) washeated to 60° C. After ˜20 h, the reaction was concentrated to give acidA-6 as a tan solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.96 (d, 2H, J=8Hz), 7.80 (m, 1H), 7.33 (d,2H1, J=8Hz), 6.84 (d, 1H, J=9Hz), 6.69 (d, 1H, J=7Hz), 3.09 (m, 4H).

Ethyl4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodo-phenylsulfonylamino)-β-alanine(A-7)

A solution of acid 15-6 (400 mg, 1.43 mmol), amine A-4 (686 mg, 1.57mmol), EDC (358 mg, 1.86 mmol), HOBT (252 mg, 1.86 mmol), NMM (632 μl,5.72 mmol) in DMF (10 ml) was stirred for ˜20 h. The reaction wasdiluted with EtOAc and then washed with sat. NaHCO₃, brine, dried(MgSO₄) and concentrated. Flash chromatography (silica, EtOAc then 5%isopropanol/EtOAc) provided amide A7 as a white solid.

TLC R_(f) =0.4 (silica, 10% isopropanol/EtOAc)

¹ H NMR (300 MHz, CD₃ OD) δ 7.79 (d, 2H, J=9Hz) 7.61 (d, 2H, J=8Hz),7.52 (d, 2H, J=9Hz), 7.29 (m, 1H), 7.27 (d, 2H, J=8Hz), 4.20 (m, 1H),3.95 (q, 2H, J=7Hz), 3.66 (dd, 1H, J=6Hz, 14Hz), 3.49 (dd, 1H, J=8Hz,13Hz), 3.01 (m, 2H), 2.86 (m, 2H), 1.08 (t, 3H, J=7Hz).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodophenyl-sulfonylamino)-.beta.alanine(A-8)

A solution of ester A-7 (200 mg, 0.3213 mmol) and 6N HCl (30 ml) washeated to 60° C. After ˜20 h, the reaction mixture was concentrated.Flash chromatography (silica, 20:20:1:1 EtOAc/EtOH/NH₄ OH/H₂ O) providedacid A-8 as a white solid.

TLC R_(f) =0.45 (silica, 20:20:1:1 EtOAc/EtOH/NH₄ OH/H₂ O)

¹ H NMR (400 MHz, DMSO) δ 8.40 (m, 1H), 8.14 (Bs, 1H), 7.81 (d, 2H,J=8Hz), 7.62 (d, 2H, J=8Hz), 7.48 (d, 2H, J=8Hz), 7.27 (m, 3H), 6.34 (d,1H, J=7Hz), 6.25 (d, 1H, J=8Hz), 5.85 (bs, 2H), 3.89 (bs, 1H), 3.35 (m,2H), 2.97 (m, 2H), 2.79 (m, 2H).

4-[2-(2-Aminopyridin-6-yl)ethyl)benzoyl-2(S)-(4-trimethylstannyl-phenylsulfonylamino-β-alanine(A-9)

A solution of iodide A-8 (70 mg, 0.1178 mmol), [(CH₃)₃ Sn]₂ (49 μl,0.2356 mmol), Pd(PPh₃)₄ (5 mg) and dioxane (7 ml) was heated to 90° C.After 2 h, the reaction was concentrated and then purified bypreparative HPLC (Delta-Pak C₁₈ 15 μM 100A°, 40×100 mm; 95:5 then 5:95H₂ O/CH₃ CN) to provide the trifluoroacetate salt. The salt wassuspended in H₂ O (10 ml), treated with NH₄ OH (5 drops) and thenlyophilized to provide amide A-9 as a white solid.

¹ H NMR (400 MHz, DMSO) δ 8.40 (m, 1H), 8.18 (d, 1H, J=8Hz), 7.67 (m,5H), 7.56 (d, 2H, J=8Hz), 7.29 (d, 2H, J=8Hz), 6.95-7.52 (m, 2H), 6.45(bs, 2H), 4.00 (m, 1H), 3.50 (m, 1H), 3.33 (m, 1H), 2.97 (m, 2H), 2.86(m, 2H).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-4-¹²⁵iodo-phenylsulfonylamino-β-alanine (A-10)

An iodobead (Pierce) was added to a shipping vial of 5 mCi of Na¹²⁵ I(Amersham, IMS30) and stirred for five. minutes at room temperature. Asolution of 0.1 mg of A-9 in 0.05 mL of 10% H₂ SO₄ /MeOH was made andimmediately added to the Na¹²⁵ I/iodobead vial. After stirring for threeminutes at room temperature, approximately 0.04-0.05 mL of NH₄ OH wasadded so the reaction mixture was at pH 6-7. The entire reaction mixturewas injected onto the HPLC for purification [Vydac peptide-protein C-18column, 4.6×250 mm, linear gradient of 10% acetonitrile (0.1% (TFA):H₂ O(0.1% TFA) to 90% acetonitrile (0.1% TFA):H₂ O (0.1% TFA) over 30minutes, 1 mL/min]. The retention time of A-10 is 17 minutes under theseconditions. Fractions containing the majority of the radioactivity werepooled, lyophilized and diluted with ethanol to give approximately 1 mCiof A-10, which coeluted on HPLC analysis with an authentic sample ofA-8.

Instrumentation: Analytical and preparative HPLC was carried out using aWaters 600E Powerline Multi Solvent Delivery System with 0.1 mL headswith a Rheodyne 7125 injector and a Waters 990 Photodiode Array Detectorwith a Gilson FC203 Microfraction collector. For analytical andpreparative HPLC, a Vydac peptide-protein C-18 column, 4.6×250 mm wasused with a C-18 Brownlee modular guard column. The acetonitrile usedfor the HPLC analyses was Fisher Optima grade. The HPLC radiodetectorused was a Beckman 170 Radioisotope detector. A Vydac C-18 protein andpeptide column, 3.9×250 mm was used for analytical and preparative HPLC.Solutions of radioactivity were concentrated using a Speedvac vacuumcentrifuge. Calibration curves and chemical concentrations weredetermined using a Hewlett Packard Model 8452A UViis Diode ArraySpectrophotometer. Sample radioactivities were determined in a PackardA5530 gamma counter.

The test procedures employed to measure αvβ3 and αvβ5 binding and thebone resorption inhibiting activity of the compounds of the presentinvention are described below.

BONE RESORPTION-PIT ASSAY

When osteoclasts engage in bone resorption, they can cause -theformation of pits in the surface of bone that they are -acting upon.Therefore, when testing compounds for their ability to inhibitosteoclasts, it is useful to measure the ability of osteoclasts toexcavate these resorption pits when the inhibiting compound is present.

Consecutive 200 micron thick cross sections from a 6 mm cylinder ofbovine femur diaphysis are cut with a low speed diamond saw (Isomet,Beuler, Ltd., Lake Bluff, Ill). Bone slices are pooled, placed in a 10%ethanol solution and refrigerated until further use.

Prior to experimentation, bovine bone slices are ultrasonicated twice,20 minutes each in H₂ O. Cleaned slices are placed in 96 well platessuch that two control lanes and one lane for each drug dosage areavailable. Each lane represents either triplicate or quadruplicatecultures. The bone slices in 96 well plates are sterilized by UVirradiation. Prior to incubation with osteoclasts, the bone slices arehydrated by the addition of 0.1 ml αMEM, pH 6.9 containing 5% fetalbovine serum and 1% penicillin/streptomycin.

Long bones from 7-14 day old rabbits (New Zealand White Hare) aredissected, cleaned of soft tissue and placed in αMEM containing 20 mMHEPES. The bones are minced using scissors until the pieces are <1 mmand transferred to a 50 ml tube in a volume of 25 ml. The tube is rockedgently by hand for 60 cycles, the tissue is sedimented for 1 min., andthe supernatant is removed. Another 25 ml of medium is added to thetissue and rocked again. The second supernatant is combined with thefirst. The number of cells is counted excluding erythrocytes (typically˜2×10⁷ cells/ml). A cell suspension consisting of 5×10⁶ /ml in αMEMcontaining 5% fetal bovine serum, 10 nM 1,25(OH)₂ D₃, andpencillin-streptomycin is prepared. 200 ml aliquots are added to bovinebone slices (200 mm×6 mm) and incubated for 2 hrs. at 37° C. in ahumidified 5% CO₂ atmosphere. The medium is removed gently with amicropipettor and fresh medium containing test compounds is added. Thecultures are incubated for 48 hrs., and assayed for c-telopeptide(fragments of the al chain of type I collagen) by Crosslaps for culturemedia (Herlev, Denmark).

Bovine bone slices are exposed to osteoclasts for 20-24 hrs and areprocessed for staining. Tissue culture media is removed from each boneslice. Each well is washed with 200 ml of H₂ O, and the bone slices arethen fixed for 20 minutes in 2.5% glutaraldehyde, 0.1 M cacodylate, pH7.4. After fixation, any remaining cellular debris is removed by 2 min.ultrasonication in the presence of 0.25 M NH₄ OH followed by 2×15 minultrasonication in H₂ O. The bone slices are immediately stained for 6-8min with filtered 1% toluidine blue and 1% borax.

After the bone slices have dried, resorption pits are counted in testand control slices. Resorption pits are viewed in a Microphot Fx (Nikon)fluorescence microscope using a polarizing Nikon IGS filter cube. Testdosage results are compared with controls and resulting IC₅₀ values aredetermined for each compound tested.

The appropriateness of extrapolating data from this assay to mammalian(including human) disease states is supported by the teaching found inSato, M., et al., Journal of Bone and Mineral Research. Vol. 5, No. 1,pp.31-40, 1990, which is incorporated by reference herein in itsentirety. This article teaches that certain bisphosphonates have beenused clinically and appear to be effective in the treatment of Paget'sdisease, hypercalcemia of malignancy, osteolytic lesions produced bybone metastases, and bone loss due to immobilization or sex hormonedeficiency. These same bisphosphonates are then tested in the resorptionpit assay described above to confirm a correlation between their knownutility and positive performance in the assay.

EIB ASSAY

Duong et al., J. Bone Miner. Res., 8: S378 (1993) describes a system forexpressing the human integrin αvβ3. It has been suggested that theintegrin stimulates attachment of osteoclasts to bone matrix, sinceantibodies against the integrin, or RGD-containing molecules, such asechistatin (European Publication 382 451), can effectively block boneresorption.

Reaction Mixture:

1. 175 μl TBS buffer (50 mM Tris.HCl pH 7.2, 150 mM NaCl, 1% BSA, 1 mMCaCl₂, 1 mM MgCl₂).

2. 25 μl cell extract (dilute with 100 mM octylglucoside buffer to give2000 cpm/25 μl).

3. ¹²⁵ I-echistatin (25 μl/50,000 cpm) (see EP 382 451).

4. 25 μl buffer (total binding) or unlabeled echistatin (non-specificbinding).

The reaction mixture was then incubated for 1 h at room temp. Theunbound and the bound αvβ3 were separated by filtration using a SkatronCell Harvester. The filters (prewet in 1.5% poly-ethyleneimine for 10mins) were then washed with the wash buffer (50 mM Tris HCl, 1 mM CaCl₂/MgCl₂, pH 7.2). The filter was then counted in a gamma counter.

SPA ASSAY

MATERIALS:

1. Wheat germ agglutinin Scintillation Proximity Beads (SPA): Amersham

2. Octylglucopyranoside: Calbiochem

3. HEPES: Calbiochem

4. NaCl: Fisher

5. CaCl₂ : Fisher

6. MgCl₂ : SIGMA

7. Phenylmethylsulfonylfluoride (PMSF): SIGMA

8. Optiplate: PACKARD

9. Compound A-10 (specific activity 500-1000 Ci/mmole)

10. test compound

11. Purified integrin receptor: α_(v) β3 was purified from 293 cellsoverexpressing α_(v) β₃ (Duong et al., J. Bone Min. Res., 8:S378, 1993)according to Pytela (Methods in Enzymology, 144:475, 1987)

12. Binding buffer: 50 mM HEPES, pH 7.8, 100 mM NaCl, 1 mM Ca²⁺ /Mg²⁺,0.5 mM PMSF

13. 50 mM octylglucoside in binding buffer: 50-OG buffer

PROCEDURE:

1. Pretreatment of SPA beads:

500 mg of lyophilized SPA beads were first washed four times with 200 mlof 50-OG buffer and once with 100 ml of binding buffer, and thenresuspended in 12.5 ml of binding buffer.

2. Preparation of SPA beads and receptor mixture

In each assay tube, 2.5 μl (40 mg/ml) of pretreated beads were suspendedin 97.5 μl of binding buffer and 20 μl of 50-OG buffer. 5 μl (˜30 ng/μl)of purified receptor was added to the beads in suspension with stirringat room temperature for 30 minutes. The mixture was then centrifuged at2,500 rpm in a Beckman GPR Benchtop centrifuge for 10 minutes at 4° C.The pellets were then resuspended in 50 μl of binding buffer and 25 μlof 50-OG buffer.

3. Reaction

The following were sequentially added into Optiplate in correspondingwells:

(i) Receptor/beads mixture (75 ml)

(ii) 25 μl of each of the following: compound to be tested, bindingbuffer for total binding or A-8 for non-specific binding (finalconcentration 1 μM)

(iii) A-10 in binding buffer (25 μl, final concentration 40 pM)

(iv) Binding buffer (125 μl)

(v) Each plate was sealed with plate sealer from PACKARD and incubatedovernight with rocking at 4° C.

4. Plates were counted using PACKARD TOPCOUNT

5. % inhibition was calculated as follows:

A=total counts

B=nonspecific counts

C=sample counts % inhibition=[{(A-B)-(C-B)}/(A-B)]/(A-B)×100

OCFORM ASSAY

Osteoblast-like cells (1.8 cells), originally derived from mousecalvaria, were plated in CORNING 24 well tissue culture plates in αMEMmedium containing ribo- and deoxyribonucleosides, 10% fetal bovine serumand penicillin-streptomycin. Cells were seeded at 40,000/well in themorning. In the afternoon, bone marrow cells were prepared from six weekold male Balb/C mice as follows:

Mice were sacrificed, tibiae removed and placed in the above medium. Theends were cut off and the marrow was flushed out of the cavity into atube with a 1 mL syringe with a 27.5 gauge needle. The marrow wassuspended by pipetting up and down. The suspension was passedthrough >100 pm nylon cell strainer. The resulting suspension wascentrifuged at 350×g for seven minutes. The pellet was resuspended, anda sample was diluted in 2% acetic acid to lyse the red cells. Theremaining cells were counted in a hemacytometer. The cells were pelletedand resuspended at 1×10⁶ cells/mL. 50 μL was added to each well of 1.8cells to yield 50,000 cells/well and 1,25-dihydroxy-vitamin D₃ (D₃) wasadded to each well to a final concentration of 10 nM. The cultures wereincubated at 37° C. in a humidified, 5% CO₂ atmosphere. After 48 h, themedium was changed. 72 h after the addition of bone marrow, testcompounds were added with fresh medium containing D₃ to quadruplicatewells. Compounds were added again after 48 h with fresh mediumcontaining D₃. After an additional 48 h., the medium was removed, cellswere fixed with 10% formaldehyde in phosphate-buffered saline for 10minutes at room temperature, followed by a 1-2 minute treatment withethanol:acetone (1:1) and air dried. The cells were then stained fortartrate resistant acid phosphatase as follows:

The cells were stained for 10-15 minutes at room temperature with 50 mMacetate buffer, pH 5.0 containing 30 mM sodium tartrate, 0.3 mg/mL FastRed Violet LB Salt and 0.1 mg/mL Naphthol AS -MX phosphate. Afterstaining, the plates were washed extensively with deionized water andair dried. The number of multinucleated, positive staining cells wascounted in each well.

αvβ5 ATTACHMENT ASSAY

Duong et al., J. Bone Miner. Res., 11: S290 (1996), describes a systemfor expressing the human αvβ5 integrin receptor.

Materials:

1. Media and solutions used in this assay are purchased from BRL/Gibco,except BSA and the chemicals are from Sigma.

2. Attachment medium: HBSS with 1 mg/ml heat-inactivated fatty acid freeBSA and 2 mM CaCl₂.

3. Glucosaminidase substrate solution: 3.75 mM p-nitrophenylN-acetyl-beta-D-glucosaminide, 0.1 M sodium citrate, 0.25% Triton, pH5.0.

4. Glycine-EDTA developing solution: 50 mM glycine, 5 mM EDTA, pH 10.5.

Methods:

1. Plates (96 well, Nunc Maxi Sorp) were coated overnight at 4° C. withhuman vitronectin (3 ug/ml) in 50 mM carbonate buffer (pH 9/.6), using100 μl/well. Plates were then washed 2× with DPBS and blocked with 2%BSA in DPBS for 2 h at room temperature. After additional washes (2×)with DPBS, plates were used for cell attachment assay.

2. 293 (αvβ5) cells were grown in MEM media in presence of 10% fetalcalf serum to 90% confluence. Cells were then lifted from dishes with 1×Trypsin/EDTA and washed 3× with serum free MEM. Cells were resuspendedin attachment medium (3×10⁵ cells/ml).

3. Test compounds were prepared as a series of dilutions at2×concentrations and added as 50 μl/well. Cell suspension was then addedas 50 μl/well. Plates were incubated at 37° C. with 55 CO₂ for 1 hour toallow attachment.

4. Non-adherent cells were removed by gently washing the plates (3×)with DPBS and then incubated with glucosaminidase substrate solution(100 μl/well), overnight at room temperature in the dark. To quantitatecell numbers, standard curve of glucosaminidase activity was determinedfor each experiment by adding samples of cell suspension directly towells containing the enzyme substrate solution.

5. The next day, the reaction was developed by addition of 185 μl/wellof glycine/EDTA solution and reading absorbance at 405 nm using aMolecular Devices V-Max plate reader. Average test absorbance values (4wells per test samples) were calculated. Then, the number of attachedcells at each drug concentration was quantitated versus the standardcurve of cells using the Softmax program.

EXAMPLE OF A PHARMACEUTICAL FORMULATION

As a specific embodiment of an oral composition, 100 mg of a compound ofthe present invention are formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size O hardgel capsule.

Representative compounds of the present invention were tested and foundto bind to human αvβ3 integrin. These compounds are generally found tohave IC₅₀ values less than about 100 nM in the SPA assay.

Representative compounds of the present invention were tested andgenerally found to inhibit≧50% the attachment of αvβ5 expressing cellsto plates coated with vitronectin at concentrations of about 1 μM.

While the invention has been described and illustrated in reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferred dosesas set forth hereinabove may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forseverity of bone disorders caused by resorption, or for otherindications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be limited only by the scopeof the claims which follow and that such claims be interpreted asbroadly as is reasonable.

What is claimed is:
 1. A compound of the formula ##STR39## wherein W is##STR40## X is selected from the group consisting of --(CH₂)_(v) --,wherein any methylene (CH₂) carbon atom is either unsubstituted orsubstituted with one or two R¹ substitutents;and a 5- or 6-memberedmonocyclic aromatic or nonaromatic ring system having 0, 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O, and S whereinthe ring nitrogen atoms are unsubstituted or substituted with one R¹substituent and the ring carbon atoms are unsubstituted or substitutedwith one or two R¹ substituents; Y is selected from the group consistingof--(CH₂)_(m) --, --(CH₂)_(m) --O--(CH₂)_(n) --, --(CH₂)_(m) --NR⁴--(CH₂)_(n) --, --(CH₂)_(m) --S--(CH₂)_(n) --, --(CH₂)_(m)--SO--(CH₂)_(n) --, --(CH₂)_(m) --SO₂ --(CH₂)_(n) --, --(CH₂)_(m)--O--(CH₂)_(n) --O--(CH₂)_(p) --, --(CH₂)_(m) --O--(CH₂)_(n) --NR⁴--(CH₂)_(p) --, --(CH₂)_(m) --NR⁴ --(CH₂)_(n) --NR⁴ --(CH₂)_(p) --,--(CH₂)_(m) --O--(CH₂)_(n) --S--(CH₂)_(p) --, --(CH₂)_(m) --S--(CH₂)_(n)--S--(CH₂)_(p) --, --(CH₂)_(m) --NR⁴ --(CH₂)_(n) --S--(CH₂)_(p) --,--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --O--(CH₂)_(p) --, --(CH₂)_(m)--S--(CH₂)_(n) --O--(CH₂)_(p) --, and --(CH₂)_(m) --S--(CH₂)_(n) --NR⁴--(CH₂)_(p) --,wherein any methylene (CH₂) carbon atom in Y, other thanin R⁴, can be substituted by one or two R³ substituents; Z is a5-membered aromatic or nonaromatic mono- or bicyclic ring system havingone heteroatom selected from the group consisting of N, O, and S, andwherein the ring system is either unsubstituted or substituted with 0,1, 2, or 3 oxo or thio substituents, and either unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of R¹⁰, R¹¹, and R¹² ; wherein R¹ is selected fromthe group consisting ofhydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloheteroalkyl, C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkylC₁₋₆ alkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃acylamino, C₁₋₃ acylamino C₁₋₈ alkyl, (C₁₋₆ alkyl)_(p) amino, (C₁₋₆alkyl)_(p) amino C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl,hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkoxycarbonyl C₁₋₆ alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy,hydroxy C₁₋₆ alkyl, C₁₋₆ alkyloxy-C₁₋₆ alkyl, nitro, cyano,trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C₁₋₈ alkyl-S(O)_(p),(C₁₋₈ alkyl)_(p) aminocarbonyl, C₁₋₈ alkyloxycarbonylamino, (C₁₋₈alkyl)_(p) aminocarbonyloxy, (aryl C₁₋₈ alkyl)_(p) amino, (aryl)_(p)amino, aryl C₁₋₈ alkylsulfonylamino, and C₁₋₈ alkylsulfonylamino; or twoR¹ substituents, when on the same carbon atom, are taken together withthe carbon atom to which they are attached to form a carbonyl group;each R³ is independently selected from the group consisting ofhydrogen,aryl, C₁₋₁₀ alkyl, aryl--(CH₂)_(r) --O--(CH₂)_(s) --, aryl--(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --, aryl--(CH₂)_(r) --C(O)--(CH₂)_(s) --,aryl--(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --, aryl--(CH₂)_(r)--N(R⁴)--C(O)--(CH₂)_(s) --, aryl--(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --,halogen, hydroxyl, oxo, trifluoromethyl, C₁₋₈ alkylcarbonylamino, arylC₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl, (C₁₋₈ alkyl)_(p) aminocarbonyl, C₁₋₆alkylcarbonyloxy, C₃₋₈ cycloalkyl, (C₁₋₆ alkyl)_(p) amino, amino C₁₋₆alkyl, arylaminocarbonyl, aryl C₁₋₅ alkylaminocarbonyl, aminocarbonyl,amninocarbonyl C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl,HC≡C--(CH₂)_(t) --, C₁₋₆ aLkyl--C≡C--(CH₂)_(t) --, C₃₋₇cycloalkyl--C≡C--(CH₂)_(t) --, aryl--C≡C--(CH₂)_(t) --, C₁₋₋₆alkylaryl--C≡--C--(CH₂)_(t) --, CH₂ ═CH--(CH₂)_(t) --, C₁₋₆alkyl--CH═CH--(CH₂)_(t) --, C₃₋₇ cycloalkyl--CH═CH--(CH₂)_(t) --,aryl--CH═CH--(CH₂)_(t) --, C₁₋₆ alkylaryl--CH═CH--(CH₂)_(t) --, C₁₋₆alkyl--SO₂ --(CH₂)_(t) --, C₁₋₆ alkylaryl--SO₂ --(CH₂)_(t) --, C₁₋₆alkoxy, aryl C₁₋₆ alkoxy, aryl C₁₋₆ alkyl, (C₁₋₆ alkyl)_(p) amino C₁₋₆alkyl, (aryl)_(p) amino, (aryl)_(p) amino C₁₋₆ alkyl, (aryl C₁₋₆alkyl)_(p) amino, (aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,arylcarbonyloxy, aryl C₁₋₆ alkylcarbonyloxy, (C₁₋₆ alkyl)_(p)aminocarbonyloxy, C₁₋₈ alkylsulfonylamiino, arylsulfonylamino, C₁₋₈alkylsulfonylamino C₁₋₆ alkyl, arylsulfonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylsulfonylamiino, aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl, C₁₋₈alkoxycarbonylamino, C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,aryloxycarbonylamino C₁₋₈ alkyl, aryl C₁₋₈ alkoxycarbonylamino, arylC₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈ alkylcarbonylamino, C₁₋₈alkylcarbonylamino C₁₋₆ alkyl, arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylcarbonylamino, aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,aminocarbonylamino C₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminocarbonylamino,(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, aminosulfonylaminoC₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminosulfonylamino, (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl, (aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino, (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonylC₁₋₆ alkyl, arylsulfonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonyl, aryl C₁₋₆alkylsulfonyl C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonyl C₁₋₆alkyl, arylcarbonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonyl, aryl C₁₋₆alkylcarbonyl C₁₋₆ alkyl, C₁₋₆ alkylthiocarbonylamino, C₁₋₆alkylthiocarbonylamino C₁₋₆ alkyl, arylthiocarbonylamino C₁₋₆ alkyl,aryl C₁₋₆ alkylthiocarbonylamino, aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆alkyl, (C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl, (aryl)_(p)aminocarbonyl C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and (arylC₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl, or two R³ substituents, whenon the same carbon atom are taken together with the carbon atom to whichthey are attached to form a carbonyl or a cyclopropyl group,wherein anyof the alkyl groups of R³ are either unsubstituted or substituted withone to three R¹ substituents, and provided that each R³ is selected suchthat in the resultant compound the carbon atom or atoms to which R³ isattached is itself attached to no more than one heteroatom; each R⁴ isindependently selected from the group consisting ofhydrogen, aryl,aminocarbonyl, C₃₋₈ cycloalkyl, amino C₁₋₆ alkyl, (aryl)_(p)aminocarbonyl, (aryl C₁₋₅ alkyl)_(p) aminocarbonyl, hydroxycarbonyl C₁₋₆alkyl, C₁₋₈ alkyl, aryl C₁₋₆ alkyl, (C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl,(aryl C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl, C₁₋₈ alkylsulfonyl, C₁₋₈alkoxycarbonyl, aryloxycarbonyl, aryl C₁₋₈ alkoxycarbonyl, C₁₋₈alkylcarbonyl, arylcarbonyl, aryl C₁₋₆ alkylcarbonyl, (C₁₋₈ alkyl)_(p)aminocarbonyl, aminosulfonyl, C₁₋₈ alkylaminosulfonyl, (aryl)_(p)aminosulfonyl, (aryl C₁₋₈ alkyl)_(p) aminosulfonyl, arylsulfonyl,arylC₁₋₆ alkylsulfonyl, C₁₋₆ alkylthiocarbonyl, arylthiocarbonyl, andaryl C₁₋₆ alkylthiocarbonyl,wherein any of the alkyl groups of R⁴ areeither unsubstituted or substituted with one to three R¹ substituents;R⁵ and R⁶ are each independently selected from the group consistingofhydrogen, C₁₋₁₀ alkyl, aryl, wherein aryl is selected from the groupconsisting of(A) phenyl, (B) naphthyl, (C) pyridyl, (D) quinolyl, (E)isoquinolyl, and (F) a 5-membered monocyclic or 5,5- or 5,6-bicyclicring system comprising at least one aromatic ring wherein the monocyclicor bicyclic ring system contains 1, 2, 3, or 4 heteroatoms selected fromthe group consisting of O, S, and N; aryl--(CH₂)_(r) --O--(CH₂)_(s) --,aryl--(CH₂)_(r) S(O)_(p) --(CH₂)_(s) --, aryl--(CH₂)_(r)--C(O)--(CH₂)_(s) --, aryl--(CH₂)_(r) --C(O)--N(R⁴)--(CH₂)_(s) --,aryl--(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --, aryl--(CH₂)_(r)--N(R⁴)--(CH₂)_(s) --, halogen, hydroxyl, C₁₋₈ alkylcarbonylamino, arylC₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl, (C₁₋₈ alkyl)_(p) aminocarbonyl, C₁₋₆alkylcarbonyloxy, C₃₋₈ cycloalkyl, (C₁₋₆ alkyl)_(p) amino, amino C₁₋₆alkyl, arylaminocarbonyl, aryl C₁₋₅ alkylaminocarbonl, aminocarbonyl,aminocarbonyl C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₋₆ alkyl,HC≡C--(CH₂)_(t) --, C₁₋₆ alkyl--C≡C--(CH₂)_(t) --, C₃₋₇cycloalkyl--C≡C--(CH₂)_(t) --, aryl--C≡C--(CH₂)_(t) --, C₁₋₆alkylaryl--C≡C--(CH₂)_(t) --, CH₂ ═CH--(CH₂)_(t) --, C₁₋₆alkyl--CH═CH--(CH₂)_(t) --, C₃₋₇ cycloalkyl--CH═CH--(CH₂)_(t) --,aryl--CH═CH--(CH₂)_(t) --, C₁₋₆ alkylaryl--CH═CH--(CH₂)_(t) --, C₁₋₆alkyl--SO₂ --(CH₂)_(t) --, C₁₋₆ alkylaryl--SO₂ --(CH₂)_(t) --, C₁₋₆alkoxy, aryl C₁₋₆ alkoxy, aryl C₁₋₆ alkyl, (C₁₋₆ alkyl)_(p) amino C₁₋₆alkyl, (aryl)_(p) amino, (aryl)_(p) amino C₁₋₆ alkyl, (aryl C₁₋₆alkyI)_(p) amino, (aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,arylcarbonyloxy, aryl C₁₋₆ alkylcarbonyloxy, (C₁₋₆ alkyl)_(p)aminocarbonyoxy, C₁₋₈ alkylsulfonylamino, arylsulfonyl amino, C₁₋₈alkylsulfonylamino C₁₋₆ alkyl, arylsulfonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylsulfonylamino, aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl, C₁₋₈alkoxycarbonylamino, C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,aryloxycarbonylamino C₁₋₈ alkyl, aryl C₁₋₈ alkoxycarbonylamino, arylC₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈ alkylcarbonylamino, C₁₋₈alkylcarbonylamino C₁₋₆ alkyl, arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylcarbonylamino, aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,aminocarbonylamino C₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminocarbonylamino,(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, aminosulfonylaminoC₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminosulfonylamino, (C₁₋₈ alkyl)_(p)aminosulfonyl amino C₁₋₆ alkyl, (aryl)_(p) aminosulfonylamino C₁₋₆alkyl, (aryl C₁₋₈ alkyl)_(p) aminosulfonyl amino, (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonylC₁₋₆ alkyl, arylsulfonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonyl, aryl C₁₋₆alkylsulfonyl C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonyl C₁₋₆alkyl, arylcarbonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonyl, aryl C₁₋₆alkylcarbonyl C₁₋₆ alkyl, C₁₋₆ alkylthiocarbonylamino, C₁₋₆alkylthiocarbonylamino C₁₋₆ alkyl, arylthiocarbonylamino C₁₋₆ alkyl,aryl C₁₋₆ alkylthiocarbonylamino, aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆alkyl, (C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl, (aryl)_(p)aminocarbonyl C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and (arylC₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl; or R⁵ and R⁶ are takentogether with the carbon atom to which they are attached to form an oxogroup,wherein any of the alkyl groups of R⁵ or R⁶ are eitherunsubstituted or substituted with one to three R¹ substituents, andprovided that each R⁵ and R⁶ are selected such that in the resultantcompound the carbon atom to which R⁵ and R⁶ are attached is itselfattached to no more than one heteroatom; R⁷ and R⁸ are eachindependently selected from the group consisting ofhydrogen, C₁₋₁₀alkyl, aryl, wherein aryl is selected from the group consisting of(A)phenyl, (B) naphthyl, (C) pyridyl, (D) quinolyl, (E) isoquinolyl, and(F) a 5-membered monocyclic or 5,5- or 5,6-bicyclic ring systemcomprising at least one aromatic ring wherein the monocyclic or bicyclicring system contains 1, 2, 3, or 4 heteroatoms selected from the groupconsisting of O, S, and N; aryl--(CH₂)_(r) --O--(CH₂)_(s) --,aryl--(CH₂)_(r) S (O)_(p) --(CH₂)_(s) --, aryl--(CH₂)_(r)--C(O)--(CH₂)_(s) --, aryl--(CH₂)_(r) --C(O)--N(R4)--(CH₂)_(s) --,aryl--(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s) --, aryl--(CH₂)_(r)--N(R⁴)--(CH₂)_(s) --, halogen, hydroxyl, C₁₋₈ alkylcarbonylino, arylC₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl, (C₁₋₈ alkyl)_(p) aminocarbonyl, C₁₋₆alkylcarbonyloxy, C₃₋₈ cycloalkyl, (C₁₋₆ alkyl)_(p) amino, amino C₁₋₆alkyl, arylaminocarbonyl, aryl C₁₋₅ alkylaminocarbonyl, aminocarbonyl,aminocarbonyl C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl,HC≡--C--(CH₂)_(t) --, C₁₋₆ alkyl--C≡C--(CH₂)_(t) --, C₃₋₇cycloalkyl--C≡C--(CH₂)_(t) --, aryl-C≡C--(CH₂)_(t) --, C₁₋₆alkylaryl--C≡C--(CH₂)_(t) --, CH₂ ═CH--(CH₂)_(t) --, C₁₋₆alkyl--CH═CH--(CH₂)_(t) --, C₃₋₇ cycloalkyl--CH═CH--(CH₂)_(t) --,aryl-CH═CH--(CH₂)_(t) --, C₁₋₆ alkylaryl--CH═CH--(CH₂)_(t) --, C₁₋₆alkyl--SO₂ --(CH₂)_(t) --, C₁₋₆ alkylaryl--SO₂ --(CH₂)_(t) --, C₁₋₆alkoxy, aryl C₁₋₆ alkoxy, aryl C₁₋₆ alkyl, (C₁₋₆ alkyl)_(p) amino C₁₋₆alkyl, (aryl)_(p) amino, (aryl)_(p) amino C₁₋₆ alkyl, (aryl C₁₋₆alkyl)_(p) amino, (aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,arylcarbonyloxy, aryl C₁₋₆ alkylcarbonyloxy, (C₁₋₆ alkyl)_(p)aminocarbonyloxy, C₁₋₈ alkylsulfonylamino, arylcarbonylamino,arylsulfonylamino, C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl, arylsulfonylaminoC₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonylamino, aryl C₁₋₆ alkylsulfonylaminoC₁₋₆ alkyl, C₁₋₈ alkoxycarbonylamino, C₁₋₈ alkoxycarbonylamino C₁₋₈alkyl, aryloxycarbonylamino C₁₋₈ alkyl, aryl C₁₋₈ alkoxycarbonylamino,aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈ alkylcarbonylamino C₁₋₆alkyl, arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonylamino, arylC₁₋₆ alkylcarbonylamino C₁₋₆ alkyl, aminocarbonylamino C₁₋₆ alkyl,arylaminocarbonylamino, (C₁₋₈ alkyl)_(p) aminocarbonylamino, (C₁₋₈alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, (aryl)_(p) aminocarbonylaminoC₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonylamino, (aryl C₁₋₈alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, aminosulfonylamino C₁₋₆ alkyl,(C₁₋₈ alkyl)_(p) aminosulfonylamino, (C₁₋₈ alkyl)_(p) aminosulfonylaminoC₁₋₆ alkyl, (aryl)_(p) aminosulfonylamino C₁₋₆ alkyl, (aryl C₁₋₈alkyl)_(p) aminosulfonylamino, (aryl C₁₋₈ alkyl)_(p) aminosulfonylaminoC₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,arylsulfonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonyl, aryl C₁₋₆alkylsulfonyl C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonyl C₁₋₆alkyl, arylcarbonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonyl, aryl C₁₋₆alkylcarbonyl C₁₋₆ alkyl, C₁₋₆ alkylthiocarbonylamino, C₁₋₆alkylthiocarbonylamino C₁₋₆ alkyl, arylthiocarbonylamino C₁₋₆ alkyl,aryl C₁₋₆ alkylthiocarbonylamino, aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆alkyl, (C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl, (aryl)_(p)aminocarbonyl C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonyl, (arylC₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl, and C₇₋₂₀ polycyclyl C₀₋₈alkyloxycarbonylamino;wherein any of the alkyl groups of R⁷ and R⁸ areeither unsubstituted or substituted with one to three R¹ substituents,and provided that each R⁷ and R⁸ are selected such that in the resultantcompound the carbon atom to which R⁷ and R⁸ are attached is itselfattached to no more than one heteroatom; R⁹ is selected from the groupconsisting ofhydrogen, C₁₋₈ alkyl, aryl, aryl C₁₋₈ alkyl, C₁₋₈alkylcarbonyloxy C₁₋₄ alkyl, aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl, C₁₋₈alkylaminocarbonylmethylene, and C₁₋₈ dialkylaminocarbonylmethylene;R¹⁰, R¹¹, and R¹² are each independently selected from the groupconsisting ofhydrogen, C₁₋₈ alkyl, aryl, halogen, hydroxyl, oxo,aminocarbonyl, C₃₋₈ cycloalkyl, amino C₁₋₆ alkyl, (aryl)_(p)aminocarbonyl, hydroxycarbonyl, (aryl C₁₋₅ alkyl)_(p) aminocarbonyl,hydroxycarbonyl C₁₋₆ alkyl, aryl C₁₋₆ alkyl, (C₁₋₆ alkyl)_(p) amino C₁₋₆alkyl, (aryl C₁₋₆ alkyl)_(p) amino C₂₋₆ alkyl, C₁₋₈ alkylsulfonyl, C₁₋₈alkoxycarbonyl, aryloxycarbonyl, aryl C₁₋₈ alkoxycarbonyl, C₁₋₈alkylcarbonyl, arylcarbonyl, aryl C₁₋₆ alkylcarbonyl, (C₁₋₈ alkyl)_(p)aminocarbonyl, aminosulfonyl, C₁₋₈ alkylaminosulfonyl, (aryl)_(p)aminosulfonyl, (aryl C₁₋₈ alkyl)_(p) aminosulfonyl, C₁₋₆ alkylsulfonyl,arylsulfonyl, aryl C₁₋₆ alkylsulfonyl, aryl C₁₋₆ alkylcarbonyl, C₁₋₆alkylthiocarbonyl, arylthiocarbonyl, aryl C₁₋₆ alkylthiocarbonyl,aryl--(CH₂)_(r) --O--(CH₂)_(s) --, aryl--(CH₂)_(r) S (O)_(p) --(CH₂)_(s)--, aryl--(CH₂)_(r) --C(O)--(CH₂)_(s) --, aryl--(CH₂)_(r)--C(O)--N(R⁴)--(CH₂)_(s) --, aryl--(CH₂)_(r) --N(R⁴)--C(O)--(CH₂)_(s)--, aryl--(CH₂)_(r) --N(R⁴)--(CH₂)_(s) --, HC≡C--(CH₂)_(t) --, C₁₋₆alkyl--C≡C--(CH₂)_(t) --, C₃₋₇ cycloalkyl--C≡C--(CH₂)_(t) --,aryl--C≡C--(CH₂)_(t) --, C₁₋₆ alkylaryl--C≡C--(CH₂)_(t) --, CH₂═CH--(CH₂)_(t) --, C₁₋₆ alkyl--CH═CH--(CH₂)_(t) --, C₃₋₇cycloalkyl--CH═CH--(CH₂)_(t) --, aryl--CH═CH--(CH₂)_(t) --, C₁₋₆alkylaryl--CH═CH--(CH₂)_(t) --, C₁₋₆ alkyl--SO₂ --(CH₂)_(t) --, C₁₋₆alkylaryl--SO₂ --(CH₂)_(t) --, C₁₋₈ alkylcarbonylamino, aryl C₁₋₅alkoxy, C₁₋₅ alkoxycarbonyl, (C₁₋₈ alkyl)_(p) aminocarbonyl, C₁₋₆alkylcarbonyloxy, (C₁₋₆ alkyl)_(p) amino, aminocarbonyl C₁₋₆ alkyl, C₁₋₆alkoxy, aryl C₁₋₆ alkoxy, (aryl)_(p) amino, (aryl)_(p) amino C₁₋₆ alkyl,(aryl C₁₋₆ alkyl)_(p) amino, (aryl C₁₋₆ alkyl)_(p) amino C₁₋₆ alkyl,arylcarbonyloxy, aryl C₁₋₆ alkylcarbonyloxy, (C₁₋₆ alkyl)_(p)aminocarbonyloxy, C₁₋₈ alkylsulfonylamino, arylsulfonylamino, C₁₋₈alkylsulfonylamino C₁₋₆ alkyl, aryIsulfonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylsulfonylamino, aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl, C₁₋₈alkoxycarbonylamino, C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,aryloxycarbonylamino C₁₋₈ alkyl, aryl C₁₋₈ alkoxycarbonylamino, arylC₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈ alkylcarbonylamino, C₁₋₈alkylcarbonylamino C₁₋₆ alkyl, arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylcarbonylamino, aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,aminocarbonylamino C₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminocarbonylamino,(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonylamino,(aryl C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, aminosulfonylaminoC₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminosulfonylamino, (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl, (aryl)_(p) aminosulfonylamino C₁₋₆ alkyl,(aryl C₁₋₈ alkyl)_(p) aminosulfonylamino, (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonylC₁₋₆ alkyl, arylsulfonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonyl, aryl C₁₋₆alkylsulfonyl C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonyl C₁₋₆alkyl, arylcarbonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonyl, aryl C₁₋₆alkylcarbonyl C₁₋₆ alkyl, C₁₋₆ alkylthiocarbonylamino, C₁₋₆alkylthiocarbonylamino C₁₋₆ alkyl, arylthiocarbonylamino C₁₋₆ alkyl,aryl C₁₋₆ alkylthiocarbonylamino, aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆alkyl, (C₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl, (aryl)_(p)aminocarbonyl C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p) aminocarbonyl, and (arylC₁₋₈ alkyl)_(p) aminocarbonyl C₁₋₆ alkyl;wherein any of the alkyl groupsof R¹⁰, R¹¹, and R¹² are either unsubstituted or substituted with one tothree R¹ substituents; wherein each m is independently an integer from 0to 6; each n is independently an integer from 0 to 6 each p isindependently an integer from 0 to 2; each r is independently an integerfrom 1 to 3; each s is independently an integer from 0 to 3; each t isindependently an integer from 0 to 3; and v is independently an integerfrom 0 to 6;and the pharmaceutically acceptable salts thereof.
 2. Thecompound of claim 1 wherein W is ##STR41## and Z is ##STR42##
 3. Thecompound of claim 2 wherein Z is selected from the group consisting of4. The compound of claim 3 wherein W is X is --(CH₂)_(v) --, wherein anymethylene (CH₂) carbon atom is either unsubstituted or substituted withone or two R¹ substitutents;Y is selected from the group consistingof--(CH₂)_(m) --, --(CH₂)_(m) --O--(CH₂)_(n) --, --(CH₂)_(m) --NR⁴--(CH₂)_(n) --, --(CH₂)_(m) --S--(CH₂)_(n) --, --(CH₂)_(m)--SO--(CH₂)_(n) --, --(CH₂)_(m) --SO₂ --(CH₂)_(n) --, --(CH₂)_(m)--O--(CH₂)_(n) --O--(CH₂)_(p) --, --(CH₂)_(m) --O--(CH₂)_(n) --NR⁴--(CH₂)_(p) --, --(CH₂)_(m) --NR⁴ --(CH₂)_(n) --NR⁴ --(CH₂)_(p) --, and--(CH₂)_(m) --NR⁴ --(CH₂)_(n) --O--(CH₂)_(p) --, wherein any carbon atomin Y, other than in R⁴, can be substituted by one or two R³substituents; and Z is ##STR43##
 5. The compound of claim 4 wherein Y isselected from the group consisting of

    (CH.sub.2).sub.m, (CH.sub.2).sub.m --S--(CH.sub.2).sub.n, and (CH.sub.2).sub.m --NR.sup.4 --(CH.sub.2).sub.n,

wherein any carbon atom in Y, other than in R⁴, can be substituted byone or two R³ substituents, and m and n are integers from 0-3, and v is0.
 6. The compound of claim 5 wherein each R³ is independently selectedfrom the group consisting ofhydrogen, fluoro, trifluoromethyl, aryl,C₁₋₈ alkyl, arylC₁₋₆ alkyl hydroxyl, oxo, arylaminocarbonyl, aryl C₁₋₅alkylaminocarbonyl, aminocarbonyl, and aminocarbonyl C₁₋₆ alkyl; andeachR⁴ is independently selected from the group consisting of hydrogen,aryl, C₃₋₈ cycloalkyl, C₁₋₈ alkyl, C₁₋₈ alkylcarbonyl, arylcarbonyl,C₁₋₆ alkylsulfonyl, arylsulfonyl, arylC₁₋₆ alkylsulfonyl, arylC₁₋₆alkylcarbonyl, C₁₋₈ alkylaminocarbonyl, arylC₁₋₅ alkylaminocarbonyl,arylC₁₋₈ alkoxycarbonyl, and C₁₋₈ alkoxycarbonyl.
 7. The compound ofclaim 6 wherein R⁶, R⁷, and R⁸ are each hydrogen and R⁵ is selected fromthe group consisting ofhydrogen, aryl, wherein aryl is selected from thegroup consisting of(A) phenyl, (B) naphthyl, (C) pyridyl, (D) quinolyl.(E) isoquinolyl, and (F) a 5-membered monocyclic or 5,5- or 5,6-bicyclicring system comprising at least one aromatic ring wherein the monocyclicor bicyclic ring system contains 1 2, 3, or 4 heteroatoms selected fromthe group consisting of O, S, and N. C₁₋₈ alkyl, aryl--C≡--C--(CH₂)_(t)--, aryl C₁₋₆ alkyl, CH₂ ═CH--(CH₂)_(t) --, and HC≡--C--(CH₂)_(t) --. 8.The compound of claim 7 wherein R⁹ is selected from the group consistingof hydrogen, methyl and ethyl.
 9. The compound of claim 8 wherein R⁹ ishydrogen.
 10. The compound of claim 6 wherein R⁵, R⁶, and R⁸ are eachhydrogen and R⁷ is selected from the group consisting ofhydrogen, aryl,wherein aryl is selected from the group consisting of(A) phenyl, (B)naphthyl, (C) pyridyl, (D) quinolyl, (E) isoquinolyl, and (F) a5-membered monocyclic or 5,5- or 5,6-bicyclic ring system comprising atleast one aromatic ring wherein the monocyclic or bicyclic ring systemcontains 1, 2, 3, or 4 heteroatoms selected from the group consisting ofO, S, and N; C₁₋₈ alkylcarbonylamino, C₁₋₈ alkylsulfonylamino,arylcarbonylamino, arylsulfonylamino, C₁₋₈ alkylsulfonylamino C₁₋₆alkyl, arylsulfonylamino C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonylamino, arylC₁₋₆ alkylsulfonylamino C₁₋₆ alkyl, C₁₋₈ alkoxycarbonylamino, C₁₋₈alkoxycarbonylamino C₁₋₈ alkyl, aryloxycarbonylamino C₁₋₈ alkyl, arylC₁₋₈ alkoxycarbonylamino, aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈alkylcarbonylamino C₁₋₆ alkyl, arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylcarbonylamino, aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,aminocarbonylamino C₁₋₆ alkyl, (C₁₋₈ alkyl)_(p) aminocarbonylamino,(C₁₋₈ alkyl)_(p) aminocarbonylamino C₁₋₆ alkyl, (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl, arylaminocarbonylamino, (aryl C₁₋₈alkyl)_(p) aminocarbonylamino, (aryl C₁₋₈ alkyl)_(p) aminocarbonylaminoC₁₋₆ alkyl, aminosulfonylamino C₁₋₆ alkyl, (C₁₋₈ alkyl)_(p)aminosulfonylamino, (C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,(aryl)_(p) aminosulfonylamino C₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino, (aryl C₁₋₈ alkyl)_(p) aminosulfonylamino C₁₋₆ alkyl,C₁₋₆ alkylthiocarbonylamino, C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,arylthiocarbonylamino C₁₋₆ alkyl, aryl C₁₋₆ alkylthiocarbonylamino, andaryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl.
 11. The compound of claim10 wherein R⁷ is selected from the group consisting ofhydrogen, aryl,wherein aryl is selected from the group consisting of(A) phenyl, (B)naphthyl, (C) pyridyl, (D) quinolyl, (E) isoquinolyl, and (F) a5-membered monocyclic or 5,5- or 5,6-bicyclic ring system comprising atleast one aromatic ring wherein the monocyclic or bicyclic ring systemcontains 1, 2, 3, or 4 heteroatoms selected from the group consisting ofO, S, and N. C₁₋₈ alkylcarbonylamino, aryl C₁₋₆ alkylcarbonylamino,arylcarbonylamino, C₁₋₈ alkylsulfonylamino, aryl C₁₋₆alkylsulfonylamino, arylsulfonylamino, C₁₋₈ alkoxycarbonylamino, arylC₁₋₈ alkoxycarbonylamino, arylaminocarbonylamino, (C₁₋₈ alkyl)_(p)aminocarbonylamino, (aryl C₁₋₈ alkyl)_(p) aminocarbonylamino, (C₁₋₈alkyl)_(p) aminosulfonylamino, and (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino.
 12. The compound of claim 11 wherein R⁹ is selectedfrom the group consisting of hydrogen, methyl, and ethyl.
 13. Thecompound of claim 12 wherein R⁹ is hydrogen.
 14. The compound of claim 6selected from the group consisting ofEthyl3(S)-(3-fluorophenyl)-3-[2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionate;Ethyl3(S)-(3-fluorophenyl)-3-[2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionate;Ethyl 3(S)-(2,3-dihydro-benzofuran-6-yl)-3-(2-oxo-3(S)-[³-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate;Ethyl3(S)-(2,3-dihydro-benzofuran-6-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate;Ethyl3(S)-(quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate;Ethyl3(S)-(quinolin-3-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate;3(S)-(3-Fluorophenyl)-3-[2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionicacid;3(S)-(3-Fluorophenyl)-3-[2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionicacid;3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(Quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(Quinolin-3-yl)-3-(2-oxo(S)-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(6-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(6-Amino-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3-(6-Methylamino-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(2-Fluoro-biphenyl-4-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(2-Oxo-2,3-dihydro-benzoxazol-6-yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(4-Ethoxy-3-fluorophenyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(5-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(5-Methoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(Ethynyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(6-Methoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3-(Furo-[2,3-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3-(2,3-Dihydrofuro[2,3-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3-(Furo-[3,2-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3-(2,3-Dihydrofuro[3,2-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(Benzimidazol-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(1H-Imidazo[4,5-c]pyridin-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid; 3(S)-(Benzoxazol-2-yl)-3-(² -oxo-³ -[³-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid;3(S)-(1-Methyl-1H-pyrazol-4-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-{2-oxo-3-[3-(6,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl}-pent-4-enoicacid;and the pharmaceutically acceptable salts thereof.
 15. The compoundof claim 14 selected from the group consistingof3(S)-(3-Fluorophenyl)-3-[2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionicacid;3(S)-(3-Fluorophenyl)-3-[2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionicacid;3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid;3(S)-(Quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;3(S)-(Quinolin-3-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionicacid;and the pharmaceutically acceptable salts thereof.
 16. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier.
 17. A pharmaceuticalcomposition made by combining a compound according to claim 1 and apharmaceutically acceptable carrier.
 18. A process for making apharmaceutical composition comprising combining a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 19. The compositionof claim 16 which further comprises an active ingredient selected fromthe group consisting ofa) an organic bisphosphonate or apharmaceutically acceptable salt or ester thereof, b) an estrogenreceptor modulator, c) a cytotoxidcantiproliferative agent, d) a matrixmetalloproteinase inhibitor, e) an inhibitor of epidermal-derived,fibroblast-derived, or platelet-derived growth factors, f) an inhibitorof VEGF, g) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1, h) acathepsin K inhibitor; and i) a prenylation inhibitor, a farnesyltransferase inhibitor or a geranylgeranyl transferase inhibitor or adual farnesyl/geranylgeranyl transferase inhibitor; and mixturesthereof.
 20. The composition of claim 19 wherein said active ingredientis selected from the group consisting ofa.) an organic bisphosphonate ora pharmaceutically acceptable salt or ester thereof, b.) an estrogenreceptor modulator, and c. a cathepsin K inhibitor; and mixturesthereof.
 21. The composition of claim 20 wherein said organicbisphosphonate or pharmaceutically acceptable salt or ester thereof isalendronate monosodium trihydrate.
 22. The composition of claim 19wherein said active ingredient is selected from the group consistingofa.) a cytotoxic/antiproliferative agent, b.) a matrixmetalloproteinase inhibitor, c.) an inhibitor of epidermal-derived,fibroblast-derived, or platelet-derived growth factors, d.) an inhibitorof VEGF, and e.) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1;and mixtures thereof.
 23. A method of eliciting an integrin receptorantagonizing effect in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of acompound according to claim
 1. 24. The method of claim 23 wherein theintegrin receptor antagonizing effect is an αvβ3 antagonizing effect.25. The method of claim 24 wherein the αvβ3 antagonizing effect isselected from the group consisting of inhibition of bone resorption,restenosis, angiogenesis, diabetic retinopathy, macular degeneration,inflammation, viral disease, and tumor growth.
 26. The method of claim25 wherein the αvβ3 antagonizing effect is the inhibition of boneresorption.
 27. The method of claim 23 wherein the integrin receptorantagonizing effect is an αvβ5 antagonizing effect.
 28. The method ofclaim 27 wherein the αvβ5 antagonizing effect is selected from the groupconsisting of inhibition of restenosis, angiogenesis, diabeticretinopathy, macular degeneration, inflammation, and tumor growth. 29.The method of claim 23 wherein the integrin receptor antagonizing effectis a dual αvβ3/αvβ5 antagonizing effect.
 30. The method of claim 29wherein the dual αvβ3/1αvβ5 antagonizing effect is selected from thegroup consisting of inhibition of bone resorption, restenosis,angiogenesis, diabetic retinopathy, macular degeneration, inflammation,viral disease, and tumor growth.
 31. The method of claim 23 wherein theintegrin antagonizing effect is an αvβ6 antagonizing effect.
 32. Themethod of claim 31 wherein the αvβ6 antagonizing effect is selected fromthe group consisting of angiogenesis, inflammatory response, and woundhealing.
 33. A method of eliciting an integrin receptor antagonizingeffect in a mammal in need thereof, comprising administering to themammal a therapeutically effective amount of the composition of claim16.
 34. A method of treating a condition mediated by antagonism of anintegrin receptor in a mammal in need thereof, comprising administeringto the mammal a therapeutically effective amount of the composition ofclaim
 16. 35. A method of inhibiting bone resorption in a mammal in needthereof, comprising administering to the mammal a therapeuticallyeffective amount of the composition of claim
 16. 36. A method ofinhibiting bone resorption in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of thecomposition of claim
 20. 37. A method of treating tumor growth in amammal in need thereof, comprising administering to the mammal atherapeutically effective amount of the composition of claim
 22. 38. Amethod of treating tumor growth in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of acompound according to claim 1 in combination with radiation therapy. 39.The compound of claim 15 which is3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3 (R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid;or apharmaceutically acceptable salt thereof.
 40. The compound of claim 15which is3(S)-(Quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid;or apharmaceutically acceptable salt thereof.